AU2011210567B2 - Small molecules for the modulation of MCL-1 and methods of modulatiing cell death, cell division, cell differentiation and methods of treating disorders - Google Patents
Small molecules for the modulation of MCL-1 and methods of modulatiing cell death, cell division, cell differentiation and methods of treating disorders Download PDFInfo
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Abstract
This invention relates to compounds which selectively bind to the survival protein MCL-1 with high affinity and selectivity, pharmaceutical compositions containing such compounds and the use of those compounds or compositions for modulating MCL-1 activity and for treating hyperproliferative disorders, angiogenesis disorders, cell cycle regulation disorders, autophagy regulation disorders, inflammatory disorders, and/or infectious disorders and/or for enhancing cellular engraftment and/or wound repair, as a sole agent or in combination with other active ingredients.
Description
WO 2011/094708 PCT/US20111/023220 SMALL MOLECULES FOR THE MODULATION OF MCL-1 AND METHODS OF MODULATING CELL DEATH, CELL DIVISION, CELL DIFFERENTIATION AND METHODS OF TREATING DISORDERS 5 The present application claims the benefit of U.S. provisional application number 61/299,803, filed January 29, 2010, which is incorporated herein by reference in its entirety. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR 10 DEVELOPMENT Funding for the present invention was provided in part by support from National Institutes of Heath under contract No. 5PO 1CA92625. Accordingly, the Government of the United States may have certain rights in and to the invention 15 BACKGROUND OF THE INVENTION Beginning with the discovery of BCL-2 at the t14;18 chromosomal breakpoint of follicular lymphoma -, the anti-apoptotic members of the BCL-2 family have emerged as key pathogenic proteins in human diseases characterized by unchecked cellular survival, such as cancer and autoimmunity. A series of anti-apoptotic 20 proteins including BCL-2, BCL-XL, BCL-w, MCL-1, BFL1/A1, and BCL-B promote cellular survival by trapping the critical apoptosis-inducing BCL-2 homology domain 3 (BH3) a -helix of pro-apoptotic BCL-2 family members 4 . Cancer cells exploit this physiologic survival mechanism through anti-apoptotic protein overexpression, establishing an apoptotic blockade that secures their immortality. To overcome this 25 potentially fatal resistance mechanism, a pharmacologic quest is underway to develop targeted therapies that bind and block BCL-2 family survival proteins. Anti-apoptotic proteins contain a hydrophobic binding pocket on their surface that engages BH3 a-helices 4
'
5 . Because Nature's solution to anti-apoptotic targeting involves selective interactions between BH3 death domains and anti-apoptotic 30 pockets 6
'
7 , molecular mimicry of the BH3 a -helix has formed the basis for developing small molecule modulators of anti-apoptotic proteins8~10. Promising compounds undergoing clinical evaluation, such as ABT-263 1 , obatoclax 9 , and AT- WO 2011/094708 PCT/US2011/023220 10112, each target three or more anti-apoptotic proteins. The development of more precise inhibitors that target individual anti-apoptotic proteins remains a significant challenge due to the often subtle differences among BH3-binding pockets. Reminiscent of the long-term goals in kinase therapeutics, anti-apoptotic inhibitors 5 with greater specificity would provide finely-tuned therapies to treat distinct diseases while potentially avoiding unwanted side-effects, such as those observed for ABT 263" and AT-101. In addition, such compounds would serve as invaluable research tools to dissect the differential biological functions of anti-apoptotic proteins. The specificity of anti-apoptotic proteins for BH3 domains is conferred by the 10 topography of the canonical binding groove and the distinctive amino acid composition of the interacting BH3 helix. Whereas some BH3 domains, such as that of pro-apoptotic BIM, can tightly engage all anti-apoptotic pockets, others are more selective like the BAD BH3 that binds BCL-2, BCL-XL, and BCL-w and the NOXA BH3 that targets MCL-1 and BFLl/Al 6 . The differential binding capacity of BH3 15 domains and their mimetics is clinically relevant, as exemplified by the close relationship between inhibitor binding spectrum and biological activity. For example, ABT-737, the prototype small molecule BH3 mimetic modeled after the BH3 domain of BAD, was designed to specifically target BCL-2 and BCL-XL' 0 , and induces apoptosis in select cancers that are driven by these proteins 14-16. However, ABT-737 20 fails to show efficacy against cancer cells that overexpress MCL-1, as this anti 15-17 apoptotic lies outside the molecule's binding spectrum . In an effort to overcome the challenge of designing precision small molecules to selectively target interaction surfaces that are comparatively large and more complex, we investigated whether Nature's selective BH3 domains could be used to rapidly identify precise small 25 molecule modulators. The development of precise inhibitors for discrete anti-apoptotic BCL-2 family proteins implicated in pathologic cell survival remains a formidable but pressing challenge. Such compounds would provide finely-tuned molecular probes to study and treat human diseases driven by specific anti-apoptotic blockades. For 30 example, anti-apoptotic MCL-1 has emerged as a major resistance factor in cancer. MCL-1 overexpression has been linked to the pathogenesis of a variety of refractory cancers, including multiple myeloma 8
'
19 , acute myeloid leukemia 16 , melanoma , and poor prognosis breast cancer . MCL-1 exerts its pro-survival activity at the mitochondrial outermembrane where it neutralizes pro-apoptotic 2 WO 2011/094708 PCT/US2011/023220 proteins such as NOXA, PUMA, BIM, and BAK. The critical role of MCL-1 in selective apoptotic resistance has been highlighted by the sensitizing effects of small interfering RNAs that downregulate MCL- 1 protein levels 22
'
2 3 . Despite the formidable challenges associated with developing precise small 5 molecule modulators of biomedically relevant protein targets, the identification of novel and selective small molecules modulators of MCL-1 is described herein. BRIEF SUMMARY OF THE INVENTION One embodiment of this invention encompasses a compound of 10 the formula: A) R1 N (Z')q R2 (Z)n x Wherein: X is =0 or -O-R3 15 R 1 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, -S-Ra, -SO 2 -R a
R
2 is hydrogen, halogen, -O-R 2 a, -NH- 2 a, -S-CN, S-R 2 a,
S-CH
2
-R
2 a or-S0 2 -Ra 20 R2a is C 1
-C
8 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted-heterocycloalkyl; 3 WO 2011/094708 PCT/US2011/023220 and R 3 is hydrogen, C-Cs alkyl substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; or B) (Z)n Z) N R6 5 R4
R
5 wherein: R4 and R are independently hydrogen, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted 10 heterocycloallyl or are taken together to form a 5-7 membered, optionally substituted, heteroaryl or heterocycloalkyl, provided that no more than one of R 4 and R 5 is hydrogen; And Ri is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or 15 substituted or unsubstituted heterocycloalkyl; or C) (z)m N N N S R7 (Z')m 4 WO 2011/094708 PCT/US2011/023220 Wherein R 7 is CH2-CO-R 7 a; -CH2-NH-SO2-R 7 a; and R 7 a is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; or 5 D) (z)m CON 0 (Z')m Wherein R8 is is -CO-R8a; -CO-NH-(CH 2 )n -Rsa; -CO-CH 2 -R a, NH-CO-NH-Ra; -NH-S0 2 -NH-R 8a; or -NH-CO-R8a; -NH-SO 2 10 R8a and R8a is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; or 15 E) (Z)p W R9 wherein R 9 is hydrogen, C 1
-C
6 alkyl, C 2
-C
6 alkeynyl, C 2
-C
6 alkynyl, -NH 2 , -NHR 9 a -NR aR I, -COH, -COR a, -COOH, or -COOR 9 a. 5 WO 2011/094708 PCT/US2011/023220
R
9 a and R 9 are independently C 1
-C
6 allkyl, C 2
-C
6 alkeynyl, C 2
-C
6 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloallkyl 5 W is -R10, -CO-R 10, 10 -CO-(CH2)n-RI" -CO-NH-R), 10 -CO-NH-(CH2)n,-RI"
-CO-NH-CO-NH-(CH
2 )n-R1", -CO-NH-SO-NH-(CH2)n-R10, -SO-(CH2)n,-R ',
-SO-NH-(CH
2 )n-R 1 0 , 15 -SO-NH-CO-NH-(CH 2 )n-R1",
-SO-NH-SO-NH-(CH
2 )n-R 10 , or NC 0
H
3 C N- R 12 * the group 0 wherein * represents the point of attachment;
R
1 0 is Z or substituted or unsubstituted aryl, substituted or 20 unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; R is Z or hydrogen, C1-C6 alkyl or -(CH2)n R12a 6 WO 2011/094708 PCT/US2011/023220 Rua is Z or substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; or F) 0 NC NH R13 5 S S R wherein R' is C 1 -Cs alkyl, C 2
-C
8 alkenyl, C 2
-C
8 alkynyl, or CI-C6 alkoxy, and R 1 4 is substituted or unsubstituted aryl, substituted or 10 unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl wherein R14 may be further substituted by Z; or G)
R
1 5 (Z)p 0 R16 15 wherein RI 5 is hydrogen, hydroxyl, halogen, -CO-(CH 2 )n-R 5 a, -CO
NH-(CH
2 )n-Rlla, -CO-NH-CO-NH-(CH 2 )-R1 5 a, -CO-NH-SO-NH (CH2)n-Risa, NH-CO-(CH2)n-Ru5a, NH-CO-NH-(CH2)n-Risa _So_ (CH2)n-Rla, -SO-NH-(CH2)n-Rla, -SO-NH-CO-NH-(CH2)n-R a,_ 20 SO-NH-SO-NH-(CH 2 )n-R 5 a,or -NH-SO 2 -R1 5 a; allyl C1-C8-Rl5a 7 WO 2011/094708 PCT/US2011/023220 R" is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; and R 16 is hydrogen, halogen, hydroxyl or substituted or 5 unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; or H) 0 R17 N R18 O N X R19 10 wherein XisOorS;
R
1 7 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl, wherein R 17 may be 15 further substituted by Z;
R
18 is hydrogen, C 1 -Cs alkyl, C 2
-C
8 alkenyl, C 2 -Cs alkynyl, or
C
1
-C
6 alkoxy, wherein R 18 may be further substituted by Z; and R 19 is hydrogen, C 1
-C
8 allkyl, C 2
-C
8 alkenyl, C 2
-C
8 alkynyl, or C 1
-C
6 alkoxywherein R 19 may be further substituted by Z; or 20 I) 8 WO 2011/094708 PCT/US2011/023220 0 R20
/Y
1 y 2 , Y2
R
21 wherein Y' is N, NH, CH or CH 2 ; y2 is O, S, or NH; 5 ---- represents an optional double bond;
R
2 0 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl, wherein R 20 may be further substituted by Z; 10 R 2 ' represents =S, =NH, -NHRla, -CHela, =NR a, or =CCO Ra; and
R
2 1a is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl, wherein R 2 1a may be further 15 substituted by Z; or J) R22 " 2 R 23 N N S R24 -N wherein
R
2 is substituted or unsubstituted aryl, substituted or unsubstituted 20 heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or 9 WO 2011/094708 PCT/US2011/023220 unsubstituted heterocycloalkyl wherein R 2 may be further substituted by Z;
R
23 is C 1 -Cs alkyl, C 2
-C
8 alkenyl, C 2
-C
8 allynyl, or CI-C 6 alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted 5 heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl wherein R 23 may be further substituted by Z; and R24 is C 1
-C
8 alkyl, C 2
-C
8 alkenyl, C 2
-C
8 allynyl, or C 1
-C
6 alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted 10 heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl wherein R 2 4 may be further substituted by Z; or K) (Z)n NH
R
25 (Z')n 15 wherein
R
2 1 is -CO-R 2 a; -CO-NH-(CH2)n -R 2 a; -CO-CH2-R 5 a, -NH-CO NH-R a; -NH-S0 2 -NH-R2a; or -NH-CO-Ra; -NH-SO 2
-R
2 5 a
R
5 a is substituted or unsubstituted aryl, substituted or unsubstituted 20 heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl wherein R 22 may be further substituted by Z; or L) 10 WO 2011/094708 PCT/US2011/023220 CI S CI N N N R26 H H wherein
R
2 6 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or 5 unsubstituted heterocycloalkyl wherein R 22 may be further substituted by Z; or and wherein 10 in each of formulas A-L: each occurrence of n is independently an integer from 0-4; each occurrence of m is independently an integer from 0-3; each occurrence of p is independently an integer from 0-2; each occurrence of q is independently an integer from 0-1; 15 each occurrence of Z, Z' and Z" is independently halogen, hydroxyl, C 1 -Cs alkyl, C 2
-C
8 alkenyl, C 2
-C
8 alkynyl, or C1-C6 alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl, 20 or M) a compound having the formula T L--T2 Q- T 2 U wherein: 11 WO 2011/094708 PCT/US2011/023220 T' represents a compound of the formula A-L; each T 2 independently represents another compound of the formula A-L which may be the same or different from TI; each Q represents a direct bond, a C 1
-C
8 alkylene linker, 5 a C 2
-C
8 alkenylene linker, a C 2
-C
8 alkynylene linker, an amide linker, or a sulfonamide linker formed by joining together a Z, Z', or Z" moiety of T with a Z, Z', or Z" moiety of each subsequent
T
2 ; and u represents an integer from 0-5 10 or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof. In some embodiments, the invention encompasses a compound 15 of having the formula M: T L-T2 u Q-T 2 JU wherein: TI represents a compound of the formula A-L; each T 2 independently represents another compound of 20 the formula A-L which may be the same or different from TI; each Q represents a direct bond, a C 1 -Cs alkylene linker, a C 2
-C
8 alkenylene linker, or a C 2
-C
8 alkynylene linker formed by joining together a Z, Z', or Z" moiety of T' with a Z, Z', or Z" moiety of each subsequent T 2 ; and 25 u represents an integer from 0-5 or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof. In some embodiments, the invention encompasses a compound having the formula M wherein u is 0 and Q is a direct bond. 12 WO 2011/094708 PCT/US2011/023220 In still other embodiments, the invention encompasses a compound having the formula M wherein u is 0 and Q is a C 1
-C
8 alkylene linker. In yet other embodiments, the invention encompasses a 5 compound having the formula M wherein u is 1 and each Q is independently a direct bond or a C 1
-C
8 alkylene linker. Representative compounds and subclasses of compounds of the invention are identified in Table 1 (including Subtables Table 1-A through Table 1-P). These compounds may be useful in the methods and compositions described herein. 10 Another aspect of the invention encompasses a pharmaceutical composition comprising one or more compounds according to Formula A-M or physiologically acceptable salts, solvates, hydrates, stereoisomers, or fusion compounds thereof and a pharmaceutically acceptable diluent or carrier. In some embodiments,the 15 pharmaceutical composition the invention encompasses a composition wherein the compound is present in a therapeutically effective amount. In still another embodiment, the pharmaceutical composition the invention further encompasses at least one further active compound. In one embodiment, the further active compound is a death receptor stimulant, an HDAC inhibitor, a 20 proteasome inhibitor, a BCL-2 family inhibitor, a kinase inhibitor, a mitotic inhibitor, a nucleoside analog, an anti-cancer monoclonal antibody, a corticosteroid, a DNA damaging agent, an antimetabolite, or other cell death-activating stimulant. Another aspect of the invention encompasses a packaged pharmaceutical composition comprising a container, the pharmaceutical composition of the invention 25 and instructions for using the pharmaceutical composition to treat a disease or condition in a mammal. Yet another aspect of the invention encompasses a method of modulating MCL-1 in a cell comprising contacting a cell with one or more compounds of the invention. In one embodiment, the activity modulated is apoptotic cell death. In 30 another embodiment, the activity modulated is autophagy. In another embodiment, the activity modulated is necrotic cell death. In another embodiment, the activity modulated is cell metabolism. In another embodiment, the activity modulated is cell division. In another embodiment, the activity modulated is transcription in a cell. In 13 WO 2011/094708 PCT/US2011/023220 another embodiment, the activity modulated is RNA Processing in a cell. In another embodiment, the activity modulated is cell differentiation. In another embodiment, the activity modulated is transcription. In another embodiment, the activity modulated is RNA processing. In another embodiment, the activity modulated is protein 5 multimerization or dissociation. Still another aspect of the invention encompasses a method of treating a hyperproliferative disorder in a mammal comprising administering to a mammal in need thereof, a therapeutically effective amount of one or more compounds of the invention. In some embodiments, the hyperproliferative disorder is cancer, including 10 but not limited to, cancer of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid or a distant metastasis of a solid tumor, a lymphoma, sarcoma, melanoma or leukemia. Yet another aspect of the invention encompasses a method of treating an angiogenesis disorder in a mammal comprising administering to a mammal in need 15 thereof, a therapeutically effective amount of one or more compounds of the invention. Still yet another aspect of the invention encompasses a method of treating an inflammatory disorder in a mammal comprising administering to a mammal in need thereof, a therapeutically effective amount of one or more compounds of the 20 invention. Another aspect of the invention encompasses a method of treating an infectious disease in a mammal comprising administering to a mammal in need thereof, a therapeutically effective amount of one or more compounds of the invention. 25 Still another aspect of the invention encompasses a method of treating a cell cycle regulation disorder in a mammal comprising administering to a mammal in need thereof, a therapeutically effective amount of one or more compounds of the invention. Yet another aspect of the invention, encompasses a method of treating an 30 autophagy regulation disorder in a mammal comprising administering to a mammal in need thereof, a therapeutically effective amount of one or more compounds of the invention. Still yet another aspect of the invention encompasses a method of treating an autoimmune disorder in a mammal comprising administering to a mammal in need 14 WO 2011/094708 PCT/US2011/023220 thereof, a therapeutically effective amount of one or more compounds of the invention. Another aspect of the invention encompasses a method of enhancing wound repair in a mammal comprising administering to a mammal in need thereof, a 5 therapeutically effective amount of one or more compounds of the invention. Yet another aspect of the invention encompasses a method of enhancing cellular engraftment in a mammal comprising administering to a mammal in need thereof, a therapeutically effective amount of one or more compounds of the invention. 10 Another aspect of the invention encompasses a method of sensitizing a cell to treatment by a secondary active ingredient comprising administering to a cell a sensitizing amount of one or more compounds of the invention. In certain embodiments, the secondary active ingredient is a death receptor stimulant, an HDAC inhibitor, a proteasome inhibitor, a BCL-2 family inhibitor, a kinase inhibitor, a 15 mitotic inhibitor, a nucleoside analog, an anti-cancer monoclonal antibody, a corticosteroid, a DNA-damaging agent, an antimetabolite, or other cell death activating stimulant.. It is noted that in this disclosure and particularly in the claims and/or paragraphs, terms such as "comprises", "comprised", "comprising" and the like can 20 have the meaning attributed to it in U.S. Patent law; e.g., they can mean "includes", "included", "including", and the like; and that terms such as "consisting essentially of' and "consists essentially of' have the meaning ascribed to them in U.S. Patent law, e.g., they allow for elements not explicitly recited, but exclude elements that are found in the prior art or that affect a basic or novel characteristic of the invention. 25 These and other embodiments are disclosed or are obvious from and encompassed by, the following Detailed Description. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1. shows the application of a selective stapled peptide in a competitive 30 binding screen to identify selective small molecules against a protein target. 15 WO 2011/094708 PCT/US20111/023220 Figure 2A shows a surface view of the BH3-binding pocket of MCL-lANAC from the X-ray structure of MCL-1 (PDB ID: 2PQK), with discrete topographic regions of the binding surface labeled A-E. 5 Figure 2B shows examples of selective small molecule binders of MCL-1ANAC engaging discrete topographic regions (labeled A-E) of the BH3-binding pocket, as rendered by molecular docking. Since certain small molecules cover distinct regions of the pocket, synthetic combinations of molecules or fragments thereof can yield a larger molecule that selectively binds a greater surface area of the BH3-binding 10 pocket. Figure 2C shows the results of a dilutional assay that revealed selective small molecule binders can be subclassified based on engaging MCL-1 through non covalent or covalent interactions. 15 Figure 2D shows that a subgroup of MCL-1 inhibitor molecules covalently reacted with C286 of MCL-1 at a novel interaction site. Figure 2E demonstrates that C286S mutagenesis abrogates binding of this subgroup 20 of molecules, confirming engagement of a novel interaction site for MCL-1 inhibition. Figure 3 shows competitive fluorescence polarization binding assays (A) and tabulated IC50 values (B) demonstrating that small molecule bioactives identified as 25 MCL-1 selective indeed exhibit preferential displacement of FITC-BID BH3 from MCL- 1ANAC compared to other anti-apoptotic proteins. Figure 4 shows competitive fluorescence polarization binding assays (A) and tabulated IC50 values (B) demonstrating that small molecules identified as MCL-1 30 selective exhibit preferential displacement of FITC-BID BH3 from MCL-1ANAC compared to other anti-apoptotic proteins. Structure-activity relationship (SAR) analysis for select derivatives of (C) Class A and (D) Class J molecular inhibitors of MCL-1, using the FITC-BID BH3/MCL-lANAC competitive fluorescence polarization binding assay. 16 WO 2011/094708 PCT/US2011/023220 Figure 5A shows that a SAHB peptide selective for MCL-1 sensitizes TRAIL induced and caspase-dependent cell death of Jurkat T-cell leukemia and OPM2 multiple myeloma cells. 5 Figure 5B shows that small molecule bioactives that target MCL-1 also sensitize the capacity of TRAIL to inhibit viability of OPM2 cells, as has been shown for selective targeting of MCL-1 with MCL-1 SAHB (Fig. 5A) and for selective knock-down of MCL-1 with siRNA. 10 Figure 5C shows a combination treatment analysis using CalcuSyn software revealing combination index values that reflect synergy between treatment with TRAIL and the identified small molecule bioactive hits that target MCL-1. 15 Figure 5D shows a combination treatment analysis using CalcuSyn software revealing combination index values that reflect synergy between treatment with TRAIL and the identified small molecule hits that target MCL-1. Figure 6 shows that selective MCL-1 inhibitor molecules block the anti-apoptotic 20 activity of MCL-1 in a BAX-mediated liposomal release assay. DETAILED DESCRIPTION OF THE INVENTION Definitions 25 In order that the invention may be more readily understood, certain terms are first defined and collected here for convenience. Other definitions appear in context throughout the application. In this disclosure, "comprises," "comprising," "containing" and "having" and the like can have the meaning ascribed to them in U.S. Patent law and can mean" 30 includes," "including," and the like; "consisting essentially of' or "consists essentially" likewise has the meaning ascribed in U.S. Patent law and the term is open-ended, allowing for the presence of more than that which is recited so long as 17 WO 2011/094708 PCT/US2011/023220 basic or novel characteristics of that which is recited is not changed by the presence of more than that which is recited, but excludes prior art embodiments. The term "halogen" refers to radicals of fluorine, chlorine, bromine and iodine. The term "alkyl" refers to a straight or branched hydrocarbon chain radical, 5 containing solely carbon and hydrogen atoms, having in the range from one up to eight carbon atoms, and which is attached to the rest of the molecule by a single bond, such as illustratively, methyl, ethyl, n-propyl 1-methylethyl (iso-propyl), n-butyl, n pentyl, and 1,1-dimethylethyl (tert-butyl). The term "cycloalkyl" denotes a non-aromatic mono or multicyclic ring 10 system having in the range of 3 up to 14 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of multicyclic cycloalkyl groups include decahydronapththyl. Examples of bridged cycloalkyl groups or sprirobicycloalkyl groups include adamantyl norbornyl, and sprio[4.4]nonyl groups. The term "alkoxy" denotes an alkyl group as defined herein attached via an 15 oxygen linkage to the rest of the molecule. Representative examples of those groups are methoxy, ethoxy, iso-propoxy, n-butoxy, and tert-butoxy. The term "cycloalkoxy" denotes a cycloalkyl group as defined herein attached via an oxygen linkage to the rest of the molecule. Representative examples of those groups are cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, and 20 cycloheptoxy. The term "aryl" refers to aromatic radicals having in the range of 6 up to 14 carbon atoms such as phenyl, naphthyl, indanyl, and biphenyl. The term "heteroaryl" refers to a stable 5- to 13-membered aromatic heterocycle having in the range of from 1 up to 4 heteroatoms from the group 25 consisting of nitrogen, phosphorus, oxygen and sulfur, which ring or ring system can be linked via a carbon atom or a nitrogen atom, if such an atom is present. For purposes of this invention, the heteroaryl ring radical may be a monocyclic, bicyclic or tricyclic ring system. Examples of such heteroaryl radicals are: pyridyl, pyridyl N oxide, pyrimidyl, pyridazinyl, pyrazinyl, thienyl, furyl, pyrrolyl, pyrazolyl, 30 imidazolyl, thiazolyl, oxazolyl or isoxazolyl, indolicenyl, indolyl, benzo[b]thienyl, benzo[b]furyl, benzothiazolyl, benzothiadiazolyl, indazolyl, quinolyl, isoquinolyl, 18 WO 2011/094708 PCT/US2011/023220 isoquinolyl, naphthyridinyl, quinazolinyl, oxadiazolyl, benzoxazolyl, tetrazoyl, triazolyl, thiadiazolyl, and benzimidazolyl. The term "heterocycloalkyl" refers to a stable 3 to 13 membered saturated or partially unsaturated heterocycle having in the range from 1 up to 4 heteroatoms from 5 the group consisting of nitrogen, phosphorus, oxygen and sulfur, which ring or ring system can be linked via a carbon atom or a nitrogen atom, if such an atom is present. For purposes of this invention, the heterocyclic ring radical may be a monocyclic, bicyclic or tricyclic ring system, which may include fused, bridged or spiro ring systems. Examples of such heterocyclyl radicals are: tetrahydropyranyl, aziridyl, 10 azepanyl, tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, piperidinyl, 1,2 dihydropyridinyl, 1,4 dihydropyridinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepinyl, oxazolinyl, thiazolinyl and 1,4 diazepinyl. The term "alkylamino" refers to an alkyl group as defined herein attached via amino linkage to the rest of the molecule. Ther term alkylamino further includes 15 dialkyl amino moieties in which two alkyl groups as define herein are attached via amino linkage to the rest of the molecule. Representative examples of those groups are methylamino and dimethylamino. Where the plural form of the word compounds, salts, polymorphs, hydrates, solvates and the like, is used herein, this is taken to mean also a single compound, 20 salt, polymdrph, isomer, hydrate, solvate or the like. The compounds of this invention may contain one or more asymmetric centers, depending upon the location and nature of the various substituents desired. Asymmetric carbon atoms may be present in the (R) or (S) configuration, resulting in racemic mixtures in the case of a single asymmetric center, and diastereomeric 25 mixtures in the case of multiple asymmetric centers. In certain instances, asymmetry may also be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compounds. Substituents on a ring may also be present in either cis or trans form. It is intended that all such configurations (including enantiomers and diastereomers), are included 30 within the scope of the present invention. Preferred compounds are those which produce the more desirable biological activity. Separated, pure or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the compounds of 19 WO 2011/094708 PCT/US2011/023220 this invention are also included within the scope of the present invention. The purification and the separation of such materials can be accomplished by standard techniques known in the art. The optical isomers can be obtained by resolution of the racemic mixtures 5 according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers. Examples of appropriate acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid. Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and/or 10 chemical differences by methods known in the art, for example, by chromatography or fractional crystallization. The optically active bases or acids are then liberated from the separated diastereomeric salts. A different process for separation of optical isomers involves the use of chiral chromatography (e.g., chiral HPLC columns), with or without conventional derivitization, optimally chosen to maximize the separation 15 of the enantiomers. Suitable chiral HPLC columns are manufactured by Diacel, e.g., Chiracel OD and Chiracel OJ among many others, all routinely selectable. Enzymatic separations, with or without derivitization, are also useful. The optically active compounds of this invention can likewise be obtained by chiral syntheses utilizing optically active starting materials. 20 The present invention also relates to useful forms of the compounds as disclosed herein, such as pharmaceutically acceptable salts, co-precipitates, metabolites, hydrates, solvates and prodrugs of all the compounds of examples. The term "pharmaceutically acceptable salt" refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound of the present invention. For example, see 25 S. M. Berge, et al. "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1-19. Pharmaceutically acceptable salts include those obtained by reacting the main compound, functioning as a base, with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, camphor sulfonic acid, oxalic acid, maleic acid, succinic acid and citric acid. 30 Pharmaceutically acceptable salts also include those in which a compound of the invention functions as an acid and is reacted with an appropriate base to form, e.g., sodium, potassium, calcium, magnesium, ammonium, and chorine salts. Those skilled in the art will further recognize that acid addition salts of the claimed 20 WO 2011/094708 PCT/US20111/023220 compounds may be prepared by reaction of a compound of the invention the appropriate inorganic or organic acid via any of a number of known methods. Alternatively, alkali and alkaline earth metal salts of acidic compounds of the invention are prepared by reacting the compounds of the invention with the 5 appropriate base via a variety of known methods. Representative salts of a compound of the invention include the conventional non-toxic salts and the quaternary ammonium salts which are formed, for example, from inorganic or organic acids or bases by means well known in the art. For example, such acid addition salts include acetate, adipate, alginate, ascorbate, 10 aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2 hydroxyethanesulfonate, itaconate, lactate, maleate, mandelate, methanesulfonate, 2 15 naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate, 3 phenylpropionate, picrate, pivalate, propionate, succinate, sulfonate, tartrate, thiocyanate, tosylate, and undecanoate. Base salts include alkali metal salts such as potassium and sodium salts, alkaline earth metal salts such as calcium and magnesium salts, and ammonium salts 20 with organic bases such as dicyclohexylamine and N-methyl-D-glucamine. Additionally, basic nitrogen containing groups may be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, 25 bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others. A solvate for the purpose of this invention is a complex of a solvent and a compound of the invention in the solid state. Exemplary solvates would include, but are not limited to, complexes of a compound of the invention with ethanol or methanol. Hydrates are a specific form of solvate wherein the solvent is water. 30 The term "subject" refers to animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In certain embodiments, the subject is a human. 21 WO 2011/094708 PCT/US2011/023220 It is also to be understood that the terminology used herein is for purposes of describing particular embodiments only, and is not intended to be limiting. As used in the specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly indicates otherwise. Thus, for 5 example, reference to "a peptide" includes multiple peptides, reference to "a spacer" includes two or more spacers. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In case of conflict, the present application, including 10 definitions will control. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference. Compounds As set forth above, the invention provides compounds which selectively bind 15 to the survival protein MCL- 1 with high affinity and selectivity. Table 1 (including Subtables Table 1-A through Table 1-P) lists of representative compounds and subclasses identified as selective or preferential MCL 1 binders based upon a small molecule competitive binding assay using FITC-MCL-1 SAHB/MCL-1ANAC and FITC-BAD BH3/BCL-XLAC interaction pairs. Figure 4C 20 and 4D tabulates select derivatives of Class A and Class J compounds that exhibit differential MCL-1 targeting activity based on chemical variation of discrete R groups. Certain compounds of Table 1 describe certain known bioactive compounds. These compounds are particularly useful in targeting MCL-1 and may be useful in the 25 treatment of diseases as described herein. Thus, in certain aspects, the compounds of Formula A-L may exclude certain compounds of Table 1. The compounds of the invention may contain one or more asymmetric centers and thus occur as racemates and racemic mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. All such isomeric forms of these 30 compounds are expressly included in the invention. The compounds of this invention may also be represented in multiple tautomeric forms, in such instances, the invention expressly includes all tautomeric forms of the compounds described herein. All such 22 WO 2011/094708 PCT/US2011/023220 isomeric forms of such compounds are expressly included in the invention. All crystal forms of the compounds described herein are expressly included in the invention. Naturally occurring or synthetic isomers can be separated in several ways 5 known in the art. Methods for separating a racemic mixture of two enantiomers include chromatography using a chiral stationary phase (see, e.g., "Chiral Liquid Chromatography," W.J. Lough, Ed. Chapman and Hall, New York (1989)). Enantiomers can also be separated by classical resolution techniques. For example, formation of diastereomeric salts and fractional crystallization can be used to separate 10 enantiomers. For the separation of enantiomers of carboxylic acids, the diastereomeric salts can be formed by addition of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, and the like. Alternatively, diastereomeric esters can be formed with enantiomerically pure chiral alcohols such as menthol, followed by separation of the diastereomeric esters and hydrolysis to 15 yield the free, enantiomerically enriched carboxylic acid. For separation of the optical isomers of amino compounds, addition of chiral carboxylic or sulfonic acids, such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid can result in formation of the diastereomeric salts. Methods of obtaining a compound of the invention include purchasing, 20 synthesizing or otherwise acquiring the compound. Synthesizing a compound of the invention is within the means of chemists of ordinary skill in the art. Methods for optimizing reaction conditions, if necessary minimizing competing by-products, are known in the art. The methods may also additionally include steps, either before or after the steps described specifically herein, to add or remove suitable protecting 25 groups in order to ultimately allow synthesis of the compounds herein. In addition, various synthetic steps may be performed in an alternate sequence or order to give the desired compounds. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the applicable compounds are known in the art and include, for example, those described in R. 30 Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3 rd Ed., John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia 23 WO 2011/094708 PCT/US2011/023220 of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions thereof. Methods of Treatment 5 In one aspect, the invention encompasses a method of modulating MCL-I in a cell comprising contacting a cell with one or more compounds of the invention. Such modulation is useful in the modulation of programmed cell death or apoptosis, autophagic cell death; necrotic cell death; cell metabolism; cell division; cell differentiation; cell migration; cell engraftment; tissue repair; RNA transcription and 10 processing; or protein multimerization or dissociation. As used herein, the term "modulation" refers to a change in activity as a direct or indirect response to the presence of at least one compound of the invention described herein, relative to the activity in the absence of the compound. The change may be an increase in activity or a decrease in activity, and may be due to the direct 15 interaction of the compound with MCL-1, or due to the interaction of the compound with one or more other factors that in turn interact with MCL-l or affect MCL-1 activity. In certain embodiments, the modulation may be the result of a covalent bond between the compound with MCL-1. In certain embodiments, the modulation may be the result of a non-covalent bond between the compound with MCL-1. In certain 20 embodiments, the modulation may be the result of a covalent bond between the compound with the established BH3 binding site of MCL-1 or with a residue of MCL 1 not associated with the established BH3 binding site of MCL-1. In certain embodiments, the modulation may be the result of a non-covalent bond between the compound with the established BH3 binding site of MCL-1 or with a residue of MCL 25 1 not associated with the established BH3 binding site of MCL-1. In still other embodiments, the modulation may be the result of a covalent bond between the compound with the C286 reside of MCL-1. In certain embodiments, the modulation may be the result of a non-covalent bond between the compound in the region of the C286 residue of MCL-1. 30 In one aspect, the invention encompasses a method of treating a hyperproliferative disorder in a mammal comprising administering to a mammal in need thereof, a therapeutically effective amount of one or more compounds of the invention. 24 WO 2011/094708 PCT/US2011/023220 As used herein the term "hyperproliferative disorder" refers to a disorder associated with an irregular or an abnormally high rate of cell division (which results in a rapid proliferation of the cells) or a blockade in the natural cell death pathway resulting in the accumulation of cells, or a combination thereof. Hyperproliferative 5 disorders include but are not limited, e.g., psoriasis, keloids, and other hyperplasias affecting the skin, benign prostate hyperplasia (BPH), solid and liquid tumors, such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases, lymphomas, sarcomas, and leukemias. 10 Still another aspect of the invention encompasses a method of treating a cell cycle regulation disorder in a mammal comprising administering to a mammal in need thereof, a .therapeutically effective amount of one or more compounds of the invention. As used herein, the term "cell cycle regulation disorder" relates to a disorder 15 of the cell cycle regulation mechanisms, observed in many malignant tumors, are directly related to uncontrolled proliferation of cancer cells. Cell cycle regulation disorders can be the result of the degradation of the regulation of one or more stages of cell growth, G 1 , S, G 2 , and M phases of the growth cycle and may include the degradation of one or more cell cycle regulators including, but not limited to, 20 p27Kipl, cdk2, cdk4, cdk6, chk1, cdc25, cyclin B, cyclin H, cyclin D, and cyclin E. Examples of breast cancer include, but are not limited to invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ. Examples of cancers of the respiratory tract include, but are not limited to 25 small-cell and non-small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma. Examples of brain cancers include, but are not limited to brain stem and hypophtalmic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumor. 30 Tumors of the male reproductive organs include, but are not limited to prostate and testicular cancer. Tumors of the female reproductive organs include, but are not limited to endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus. 25 WO 2011/094708 PCT/US2011/023220 Tumors of the digestive tract include, but are not limited to anal, colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal, small-intestine, and salivary gland cancers. Tumors of the urinary tract include, but are not limited to bladder, penile, 5 kidney, renal pelvis, ureter, urethral and human papillary renal cancers. Eye cancers include, but are not limited to intraocular melanoma and retinoblastoma. Examples of liver cancers include, but are not limited to hepatocellular carcinoma (liver cell carcinomas with or without fibrolamellar variant), 10 cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma. Skin cancers include, but are not limited to squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer. 15 Head-and-neck cancers include, but are not limited to laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal cancer, lip and oral cavity cancer and squamous cell. Lymphomas include, but are not limited to AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin's disease, and lymphoma of the central nervous system. 20 Sarcomas include, but are not limited to sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma. Leukemias include, but are not limited to acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous 25 leukemia, and hairy cell leukemia. In one aspect, the invention encompasses a method of treating angiogenesis in a mammal comprising administering to a mammal in need thereof, a therapeutically effective amount of one or more compounds of the invention. As used herein the term "angiogenesis" refers to a disorder associated with 30 excessive and/or abnormal angiogenesis. Inappropriate and ectopic expression of angiogenesis can be deleterious to an organism. A number of pathological conditions are associated with the growth of extraneous blood vessels. These include, e.g., diabetic retinopathy, ischemic retinal vein occlusion, and retinopathy of prematurity (Aiello et al. New Engl. J. Med. 1994, 26 WO 2011/094708 PCT/US2011/023220 331, 1480; Peer et al. Lab. Invest. 1995, 72, 638), age-related macular degeneration (AMD; see, Lopez et al. Invest. Opththalmol. Vis. Sci. 1996, 37, 855), neovascular glaucoma, psoriasis, retrolental fibroplasias, angiofibroma, inflammation, rheumatoid arthritis (RA), restenosis, in-stent restenosis, vascular graft restenosis, etc. In addition, 5 the increased blood supply associated with cancerous and neoplastic tissue, encourages growth, leading to rapid tumor enlargement and metastasis. Moreover, the growth of new blood and lymph vessels in a tumor provides an escape route for renegade cells, encouraging metastasis and the consequence spread of the cancer. Thus, compounds of the present invention can be utilized to treat and/or prevent any 10 of the aforementioned angiogenesis disorders, e.g., by inhibiting and/or reducing blood vessel formation; by inhibiting, blocking, reducing, decreasing, etc. endothelial cell proliferation or other types involved in angiogenesis, as well as causing cell death or apoptosis of such cell types. Another aspect of the invention encompasses a method of treating an 15 infectious disease by blocking pathogen or infected cell survival in a mammal comprising administering to a mammal in need thereof, a therapeutically effective amount of one or more compounds of the invention. Examples of infectious diseases include, but are not limited to, AIDS, Alveolar Hydatid Disease (AHD, Echinococcosis), Amebiasis (Entamoeba histolytica 20 Infection), Angiostrongylus Infection, Anisakiasis, Anthrax, Babesiosis (Babesia Infection), Balantidium Infection (Balantidiasis), Baylisascaris Infection (Raccoon Roundworm), Bilharzia (Schistosomiasis), Blastocystis hominis Infection (Blastomycosis), Boreliosis, Botulism, Brainerd Diarrhea, Brucellosis, BSE (Bovine Spongiform Encephalopathy), Candidiasis, Capillariasis (Capillaria Infection), CFS 25 (Chronic 'Fatigue Syndrome), Chagas Disease (American Trypanosomiasis), Chickenpox (Varicella-Zoster virus), Chlamydia pneumoniae Infection, Cholera, Chronic Fatigue Syndrome, CJD (Creutzfeldt-Jakob Disease), Clonorchiasis (Clonorchis Infection), CLM (Cutaneous Larva Migrans, Hookworm Infection), Coccidioidomycosis, Conjunctivitis, Coxsackievirus A16 (Hand, Foot and Mouth 30 Disease), Cryptococcosis, Cryptosporidium Infection (Cryptosporidiosis), Culex mosquito (Vector of West Nile Virus), Cutaneous Larva Migrans (CLM), Cyclosporiasis (Cyclospora Infection), Cysticercosis (Neurocysticercosis), Cytomegalovirus Infection, Dengue/Dengue Fever, Dipylidium Infection (Dog and Cat Flea Tapeworm), Ebola Virus Hemorrhagic Fever, Echinococcosis (Alveolar 27 WO 2011/094708 PCT/US2011/023220 Hydatid Disease), Encephalitis, Entamoeba coli Infection, Entamoeba dispar Infection, Entamoeba hartmanni Infection, Entamoeba histolytica Infection (Amebiasis), Entamoeba polecki Infection, Enterobiasis (Pinworm Infection), Enterovirus Infection (Non-Polio), Epstein-Barr Virus Infection, Escherichia coli 5 Infection, Foodborne Infection, Foot and mouth Disease, Fungal Dermatitis, Gastroenteritis, Group A streptococcal Disease, Group B streptococcal Disease, Hansen's Disease (Leprosy), Hantavirus Pulmonary Syndrome, Head Lice Infestation (Pediculosis), Heliobacter pylori Infection, Hematologic Disease, Hendra Virus Infection, Hepatitis (HCV, HBV), Herpes Zoster (Shingles), HIV Infection, Human 10 Ehrlichiosis, Human Parainfluenza Virus Infection, Influenza, Isosporiasis (Isospora Infection), Lassa Fever, Leishmaniasis, Kala-azar (Kala-azar, Leishmania Infection), Lice (Body lice, Head lice, Pubic lice), Lyme Disease, Malaria, Marburg Hemorrhagic Fever, Measles, Meningitis, Mosquito-borne Diseases, Mycobacterium avium Complex (MAC) Infection, Naegleria Infection, Nosocomial Infections, 15 Nonpathogenic Intestinal Amebae Infection, Onchocerciasis (River Blindness), Opisthorciasis (Opisthorcis Infection), Parvovirus Infection, Plague, PCP (Pneumocystis carinii Pneumonia), Polio, Q Fever, Rabies, Respiratory Syncytial Virus (RSV) Infection, Rheumatic Fever, Rift Valley Fever, River Blindness (Onchocerciasis), Rotavirus Infection, Roundworms Infection, Salmonellosis, 20 Salmonella Enteritidis, Scabies, Shigellosis, Shingles, Sleeping Sickness, Smallpox, Streptococcal Infection, Tapeworm Infection (Taenia Infection), Tetanus, Toxic Shock Syndrome, Tuberculosis, Ulcers (Peptic Ulcer Disease), Valley Fever, Vibrio parahaemolyticus Infection, Vibrio vulnificus Infection, Viral Hemorrhagic Fever, Warts, Waterborne infectious Diseases, West Nile Virus Infection (West Nile 25 Encephalitis), Whooping Cough, Yellow Fever, tuberculosis, leprosy, mycobacteria induced meningitis, Chagas disease, effects of Shiga-like toxin resulting from Staphylococcus infection, meningococcal infection, and infections from Borrelia burgdorferi or Treponema pallidum. Yet another aspect of the invention encompasses a method of treating an 30 autophagy regulation disorder in a mammal comprising administering to a mammal in need thereof, a therapeutically effective amount of one or more compounds of the invention. As used herein, the term "autophagy regulation disorder" relates to a dissorder of the autophagy system of a cell i.e. the self-digestion by a cell through the action of 28 WO 2011/094708 PCT/US2011/023220 enzymes originating within the same cell including, but not limited to, chaperone mediated autophagy, macroautophagy, microautophagy. Disorders of autophagy regulation include but are not limited to, Danon disease X-linked myopathy with excessive autophagy, Infantile autophagic vacuolar myopathy, Childhood autophagic 5 vacuolar myopathy, Adult-onset autophagic vacuolar myopathy with multiorgan involvement, LGMD 1A, Toxic myopathy, Inflammatory myopathies, Hypokalemic myopathy, Acid maltase deficiency, Inflammatory bowel disease associations, Autophagy 16-like 1 (ATG16L1), LRG47, and autophagy-mediated survival of cancer cells or cancer stem cells to escape chemotherapy or radiation treatments. 10 Still yet another aspect of the invention provides a method of treating an autoimmune disorder in a mammal comprising administering to a mammal in need thereof, a therapeutically effective amount of one or more compounds of the invention. Examples of autoimmune disorders include, but are not limited to, allergic 15 bronchopulmonary aspergillosis; autoimmune hemolytic anemia; acanthosis nigricans; allergic contact dermatitis; Addison's disease; atopic dermatitis; alopecia greata; alopecia universalis; amyloidosis; anaphylactoid purpura; anaphylactoid reaction; aplastic anemia; angioedema, hereditary; angioedema, idiopathic; ankylosing spondylitis; arteritis, cranial; arteritis, giant cell; arteritis, Takayasu's; 20 arteritis, temporal; asthma; a-telangiectasia; autoimmune oophoritis; autoimmune orchitis; autoimmune polyendocrine failure; Behcet's disease; Berger's disease; Buerger's disease; bullous pemphigus; candidiasis, chronic mucocutaneous; Caplan's syndrome; post-myocardial infarction syndrome; post-pericardiotomy syndrome; carditis; celiac sprue; Chagas's disease; Chediak-Higashi syndrome; Churg-Strauss 25 disease; Cogan's syndrome; cold agglutinin disease; CREST syndrome; Crohn's disease; cryoglobulinemia; cryptogenic fibrosing alveolitis; dermatitis herpetifomis; dennatomyositis; diabetes mellitus; Diamond-Blackfan syndrome; DiGeorge syndrome; discoid lupus erythematosus; eosinophilic fascitis; episcleritis; drythema elevatum diutinum; erythema marginatum; erythema multiforme; erythema nodosum; 30 familial Mediterranean fever; Felty's syndrome; fibrosis pulmonary; glomerulonephritis, anaphylactoid; glomerulonephritis, autoimmune; glomerulonephritis, post-streptococcal; glomerulonephritis, post-transplantation; glomerulopathy, membranous; Goodpasture's syndrome; graft-vs.-host disease; granulocytopenia, immune-mediated; granuloma annulare; granulomatosis, allergic; 29 WO 2011/094708 PCT/US2011/023220 granulomatous myositis; Grave's disease; Hashimoto's thyroiditis; hemolytic disease of the newborn; hemochromatosis, idiopathic; Henoch-Schoenlein purpura; hepatitis, chronic active and chronic progressive; histiocytosis X; hypereosinophilic syndrome; idiopathic thrombocytopenic purpura; Job's syndrome; juvenile dermatomyositis; 5 juvenile rheumatoid arthritis juvenile chronic arthritis); Kawasaki's disease; keratitis; keratoconjunctivitis sicca; Landry-Guillain-Barre-Strohl syndrome; leprosy, lepromatous; Loeffler's syndrome; Lyell's syndrome; Lyme disease; lymphomatoid granulomatosis; mastocytosis, systemic; mixed connective tissue disease; mononeuritis multiplex; Muckle-Wells syndrome; mucocutaneous lymph node 10 syndrome; mucocutaneous lymph node syndrome; multicentric reticulohistiocytosis; multiple sclerosis; myasthenia gravis; mycosis fungoides; necrotizing vasculitis, systemic; nephrotic syndrome; overlap syndrome; panniculitis; paroxysmal cold hemoglobinuria; paroxysmal nocturnal hemoglobinuria; pemphigoid; pemphigus; pemphigus erythematosus; pemphigus foliaceus; pemphigus vulgaris; pigeon 15 breeder's disease; pneumonitis, hypersensitivity; polyarteritis nodosa; polymyalgia rheumatica; polymyositis; polyneuritis, idiopathic; Portuguese familial polyneuropathies; pre-eclampsia/eclampsia; primary biliary cirrhosis; progressive systemic sclerosis (scleroderma); psoriasis; psoriatic arthritis; pulmonary alveolar proteinosis; pulmonary fibrosis, Raynaud's phenomenon/syndrome; Reidel's 20 thyroiditis; Reiter's syndrome, relapsing polychrondritis; rheumatic fever; rheumatoid arthritis; sarcoidosis; scleritis; sclerosing cholangitis; serum sickness; Sezary syndrome; Sjogren's syndrome; Stevens-Johnson syndrome; Still's disease; subacute sclerosing panencephalitis; sympathetic ophthalmia; systemic lupus erythematosus; transplant rejection; ulcerative colitis; undifferentiated connective tissue disease; 25 urticaria, chronic; urticaria, cold; uveitis; vitiligo; Weber-Christian disease; Wegener's granulomatosis; and Wiskott-Aldrich syndrome. In another aspect, the invention provides a method of enhancing cellular engraftment in a subject comprising administering to a subject in need thereof of a 30 therapeutically effective amount of one or more compounds of the invention. As used herein the phrase "enhancing cellular engraftment" refers to an improvement in efficiency, quality or rapidity of cell transplantation which may result from improved homing to the target tissue, improved adhesion, reduced rejection and the like. Methods for assessing cell engraftment potential include, for example, cell 30 WO 2011/094708 PCT/US20111/023220 migration and other in vitro techniques, and histological, immunological and/or radiological assessment of tissues and organs from actual in-vivo transplantation. In certain aspects, the term "enhancing cellular engraftment" also includes, but is not limited to, the treatment of a disorder in which the subject is treated with cells, such as 5 in the context of bone marrow transplantation, stem cell replacement, and skin engraftment. In another aspect, the invention provides a method of enhancing wound repair in a subject comprising administering to a subject in need thereof of a therapeutically 10 effective amount of one or more compounds of the invention. As used herein the term, "enhancing wound repair" includes, but is not limited to, the formation of granulation tissue; of wound contraction; and/or the induction of epithelialization (i.e., the generation of new cells in the epithelium). Wound repair is conveniently measured by decreasing wound area. In certain aspects, the term 15 "enhancing wound repair" also includes, but is not limited to, the treatment a disorder in which the subject is being treated for tissue damage, either internal or external, such that the goal is to restore organ or tissue integrity. In another aspect, the invention provides a method of treating an 20 inflammatory condition in a subject comprising administering to a subject in need thereof an effective amount of a composition comprising a compound of the invention or a pharmaceutically acceptable salt thereof. As used herein, the term "inflammatory condition" refers to a condition or disorder associated with one or more aberrant physiological processes or other 25 physiological responses (such as responses to an injurious or noxious stimulus) which result in a pathophysiological state of inflammation. An inflammatory condition may be either an acute or chronic inflammatory condition, which can result from infections or non-infectious causes. Various infectious causes include meningitis, encephalitis, uveitis, colitis, tuberculosis, dermatitis, and adult respiratory distress syndrome. Non 30 infectious causes include trauma (burns, cuts, contusions, crush injuries), autoimmune diseases, and organ rejection episodes. Thus, in specific aspects, an inflammatory condition results from a condition selected from the group that includes: atherosclerosis (arteriosclerosis); autoimmune conditions, such as multiple sclerosis, 31 WO 2011/094708 PCT/US2011/023220 systemic lupus erythematosus, polymyalgia rheumatica (PMR), gouty arthritis, degenerative arthritis, tendonitis, bursitis, psoriasis, fibrosis, arthrosteitis, rheumatoid arthritis and other forms of inflammatory arthritis, Sjogren's Syndrome, progressive systemic sclerosis (scleroderma), ankylosing spondylitis, polymyositis, 5 dermatomyositis, pemphigus, pemphigoid, Type I diabetes mellitus, myasthenia gravis, Hashimoto's thyroditis, Graves' disease, Goodpasture's disease, mixed connective tissue disease, sclerosing cholangitis, inflammatory bowel disease including Crohn's Disease (regional enteritis) and ulcerative colitis, pernicious anemia, inflammatory dermatoses; usual interstitial pneumonitis (UIP), asbestosis, 10 silicosis, bronchiectasis, berylliosis, talcosis, all forms of pneumoconiosis, sarcoidosis (in the lung and in any other organ), desquamative interstitial pneumonia, lymphoid interstitial pneumonia, giant cell interstitial pneumonia, cellular interstitial pneumonia, extrinsic allergic alveolitis, Wegener's granulomatosis and related forms of angiitis (temporal arteritis and polyarteritis nodosa); sepsis; inflammatory 15 dermatoses not presumed to be autoimmune; chronic active hepatitis; delayed-type hypersensitivity reactions (e.g., poison ivy dermatitis); pneumonia or other respiratory tract inflammation due to any cause; Adult Respiratory Distress Syndrome (ARDS) from any etiology; encephalitis with inflammatory edema; immediate hypersensitivity reactions including, but not limited to, asthma, hayfever, cutaneous allergies, acute 20 anaphylaxis; diseases involving acute deposition of immune complexes, including, but not limited to, rheumatic fever, acute and/or chronic glomerulonephritis due to any etiology, including specifically post-infectious (e.g., post-Streptococcal) glomerulonephritis, acute exacerbations of Systemic Lupus Erythematosus; pyelonephritis; cellulitis; cystitis; acute and/or chronic cholecystitis; and conditions 25 producing transient ischemia anywhere along the gastrointestinal tract, bladder, heart, or other organ, especially those prone to rupture; sequelae of organ transplantation or tissue allograft, including allograft rejection in the acute time period following allogeneic organ or tissue transplantation and chronic host-versus-graft rejection. The term "inflammatory condition" also includes appendicitis, arteritis, blepharitis, 30 bronchiolitis, bronchitis, cervicitis, cholangitis, chorioamnionitis, conjunctivitis, dacryoadenitis, dermatomyositis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, gingivitis, ileitis, iritis, laryngitis, myelitis, myocarditis, nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, pharyngitis, pleuritis, 32 WO 2011/094708 PCT/US20111/023220 phlebitis, pneumonitis, proctitis, prostatitis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tonsillitis, uveitis, vaginitis, vasculitis, vulvitis, and vulvovaginitis, angitis, chronic bronchitis, osteomylitis, optic neuritis, temporal arteritis, transverse myelitis, necrotizing fascilitis, hepatitis, and necrotizing enterocolitis. 5 In a specific aspect, the invention encompasses a method of targeting MCL-1 in a cell comprising contacting a cell with one or more compounds selected from gossypol, celastrol, manoalide, u73122, bithionol and hexachlorophene. Such targeting may useful in the modulation of programmed cell death or apoptosis, autophagic cell death; necrotic cell death; cell metabolism; cell division; cell 10 differentiation; RNA transcription and processing; or protein multimerization or dissociation. As used herein, ' the term "targeting" refers to the direct interaction of the compound with MCL-1, or to the interaction of the compound with one or more other factors that in turn interact with MCL-1 or affect MCL-1 activity. 15 Administration In certain embodiments, a compound of the invention or a pharmaceutically acceptable salt, solvate or hydrate thereof is administered to the subject in a 20 pharmaceutically-acceptable formulation. In certain embodiments, a compound of the invention or a pharmaceutically acceptable salt, solvate or hydrate thereof or an a compound of the invention pharmaceutical composition is suitable for topical, intravenous, parental, or oral administration. The methods of the invention further include administering to a subject a therapeutically effective amount of a compound 25 of the invention or a pharmaceutically acceptable salt, solvate or hydrate thereof . The phrase "pharmaceutically acceptable" refers to a compound of the invention, compositions containing a compound of the invention, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, 30 allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. 33 WO 2011/094708 PCT/US2011/023220 The phrase "pharmaceutically-acceptable carrier" includes pharmaceutically acceptable material, composition or vehicle, involved in carrying or transporting the subject chemical from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with 5 the other ingredients of the formulation and not injurious to the patient. Methods of preparing these compositions include the step of bringing into association a compound of the invention or a pharmaceutically acceptable salt, solvate or hydrate thereof with the carrier and, optionally, one or more accessory ingredients. These compositions may also contain adjuvants such as preservatives, wetting agents, 10 emulsifying agents and dispersing agents. Regardless of the route of administration selected, a compound of the invention, which may be used in a suitable salt, solvate, or hydrate form, and/or the pharmaceutical compositions of a compound of the invention, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those 15 of skill in the art. Formulations are provided to a subject in an effective amount. The term "effective amount" includes an amount effective, at dosages and for periods of time necessary, to achieve the desired result. An effective amount of a compound of the invention may vary according to factors such as the disease state, age, and weight of 20 the subject, and the ability of the compound to elicit a desired response in the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response. The effective amount is generally determined by the physician on a case-by case basis and is within the skill of one in the art. As a rule, the dosage for in vivo therapeutics or diagnostics will vary. Several factors are typically taken into account 25 when determining an appropriate dosage. These factors include age, sex and weight of the patient, the condition being treated, and the severity of the condition. In addition, an effective amount is preferably selected to minimize adverse side effects. For example, an effective amount of a compound of the invention is preferably selected to treat or prevent a disorder as disclosed herein, while minimizing side 30 effects such as hypotension. Suitable dosages and formulations of a compound of the invention or a pharmaceutically acceptable salt, solvate or hydrate thereof can be empirically 34 WO 2011/094708 PCT/US2011/023220 determined by the administering physician. Standard texts, such as Remington: The Science and Practice of Pharmacy, 17th edition, Mack Publishing Company, and the Physician's Desk Reference, each of which are incorporated herein by reference, can be consulted to prepare suitable compositions and doses for administration. A 5 determination of the appropriate dosage is within the skill of one in the art given the parameters for use described herein. Standard texts, such as Remington: The Science and Practice of Pharmacy, 17th edition, Mack Publishing Company, incorporated herein by reference, can be consulted to prepare suitable compositions and formulations for administration, 10 without undue experimentation. Suitable dosages can also be based upon the text and documents cited herein. A determination of the appropriate dosages is within the skill of one in the art given the parameters herein. In terms of treatment, an effective amount is an amount that is sufficient to palliate, ameliorate, stabilize, reverse or slow the progression of an inflammatory 15 condition or other disorder as disclosed herein, or the symptoms thereof. A therapeutically effective amount can be provided in one or a series of administrations. In terms of an adjuvant, an effective amount is one sufficient to enhance the anti inflammatory or immune response to the anti-inflammatory or immunogen. The effective amount is generally determined by the physician on a case-by-case basis and 20 is within the skill of one in the art. As a rule, the dosage for in vivo therapeutics or diagnostics will vary. Several factors are typically taken into account when determining an appropriate dosage. These factors include age, sex and weight of the patient, the condition being treated, the severity of the condition and the method of administration. 25 The dosage of a compound of the invention or a pharmaceutically acceptable salt, solvate or hydrate thereof can vary from about 0.01 mg to about 1,000 mg per day; about 0.1 mg to about 250 mg per day; about 0.5 mg to about 100 mg per day; or about 1 to about 5 mg per day. Ascertaining dosage ranges is well within the skill of one in the art. The dosage of a compound of the invention or a pharmaceutically 30 acceptable salt, solvate or hydrate thereof can range from about 0.001 to 25 mg/kg of body weight. Such dosages may vary, for example, depending on whether multiple administrations are given, tissue type and route of administration, the condition of the 35 WO 2011/094708 PCT/US2011/023220 individual, the desired objective and other factors known to those of skill in the art. Administrations can be conducted infrequently, or on a regular weekly basis until a desired, measurable parameter is detected, such as diminution of disease symptoms. Administration can then be diminished, such as to a biweekly or monthly basis, as 5 appropriate. A therapeutically effective amount can be administered in one or more doses. The term "administration" or "administering" includes routes of introducing the compound(s) to a subject to perform their intended function. Examples of routes of administration which can be used include injection (subcutaneous, intravenous, 10 parenterally, intraperitoneally, intrathecal), oral, inhalation, rectal and transdermal. The phrases "parenteral administration" and "administered parenterally" as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, 15 intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrastemal injection and infusion. The phrases "systemic administration," "administered systemically", "peripheral administration" and "administered peripherally" as used herein mean the administration of a compound(s), drug or other material, such that it enters the 20 patient's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration. Such dosages may vary, for example, depending on whether multiple administrations are given, tissue type and route of administration, the condition of the individual, the desired objective and other factors known to those of skill in the art. 25 Available routes of administration include subcutaneous, intramuscular, intraperitoneal, intradermal, oral, intranasal, intrapulmonary (i.e., by aerosol), intravenously, intramuscularly, subcutaneously, intracavity, intrathecally or transdermally, alone or in combination with other pharmaceutical agents. A cell can be contacted with a composition including a compound of the 30 invention, in certain embodiments in vivo or, in certain embodiments, in vitro. Contacting a cell in vivo can include administration of the composition to a subject, or to a tissue, such that a cell is contacted with a compound of the invention. Contacting 36 WO 2011/094708 PCT/US2011/023220 a cell in vitro can include, e.g., contacting the cell with a compound of the invention, or a composition consisting essentially of a compound of the invention, directly or by addition of irinadalone or the composition to a growth medium for the cell. 5 Additional/Secondary Therapeutic Agents The compounds and compositions of the invention can be administered with one or more additional additional therapeutic agents either separately or in the same formulation as a compound of the invention. In certain embodiments the compounds and compositions of the invention are 10 useful in sensitizing a cell or a subject to one or more secondary therapeutic agents. In such embodiments, the invention provides a method for sensitizing a cell to a secondary therapeutic agent comprising administering to said cell a sensitizing amount of one or more compound of the invention. A sensitizing amount may be any amount capable of generating a greater response by the cell to the secondary 15 therapeutic agent as compared to the response by the cell without a compound or composition of the invention. In certain embodiments a sensitizing amount is a therapeutically effective amount. In other embodiments, a sensitizing amount is less than a therapeutically effective amount. The compounds and compositions of the invention can be administered with 20 one or more additional therapeutic agents either separately or in the same formulation as a compound of the invention. Additional Therapeutic agents include, but are not limited to antacids, antibiotics, antiemetic agents, antidepressants, and antifungal agents, anti inflammatory agents, antiviral agents, anticancer agents, immunomodulatory agents, 25 beta-interferons, hormones or cytokines. Additional Therapeutic agents further include, but are not limited to death receptor stimulants (eg. TRAIL), HDAC inhitor (eg. SAHA), proteasome inhibitor (eg. Bortezomib), BCL-2 family inhibitor (eg. ABT-737, ABT-263, obatoclax), kinase inhibitor (e.g. Gleevac, Raf inhibitor), mitotic inhibitors (e.g. Taxol), 30 nucleoside analogs (e.g. Gemcitabine), and anti-cancer monoclonal antibodies (e.g. cetuximab), corticosteroids (e.g. dexamethasone), DNA-damaging agents (e.g. cisplatin), antimetabolites (e.g. methotrexate). 37 WO 2011/094708 PCT/US2011/023220 The compounds of the invention can be formulated in combination with antacids. For example, they can be formulated with aluminum carbonate, aluminum hydroxide, bismuth subsalicylate, calcium carbonate, calcium hydroxide, calcium phosphate, dihydroxyaluminum sodium carbonate, magnesium hydroxide, magnesium 5 oxide, magnesium trisilicate, sodium bicarbonate, simethicone, glycine, or combinations thereof. The compounds of the invention can be formulated in combination with antibiotics. For example, they can be formulated with a macrolide (e.g., tobramycin), a cephalosporin (e.g., cephalexin , cephradine , cefuroxime , cefprozil, cefaclor, 10 cefixime or cefadroxil), a clarithromycin (e.g., clarithromycin), an erythromycin (e.g., erythromycin), a penicillin (e.g., penicillin V) or a quinolone (e.g., ofloxacin, ciprofloxacin or norfloxacin), aminoglycoside antibiotics (e.g., apramycin, arbekacin, bambermycins, butirosin, dibekacin, neomycin, neomycin, undecylenate, netilmicin, paromomycin, ribostamycin, sisomicin, and spectinomycin), amphenicol antibiotics 15 (e.g., azidamfenicol, chloramphenicol, florfenicol, and thiamphenicol), ansamycin antibiotics (e.g., rifamide and rifampin), carbacephems (e.g., loracarbef), carbapenems (e.g., biapenem and imipenem), cephalosporins (e.g., cefaclor, cefadroxil, cefamandole, cefatrizine, cefazedone, cefozopran, cefpimizole, cefpiramide, and cefpirome), cephamycins (e.g., cefbuperazone, cefmetazole, and cefininox), 20 monobactams (e.g., aztreonam, carumonam, and tigemonam), oxacephems (e.g., flomoxef, and moxalactam), penicillins (e.g., amdinocillin, amdinocillin pivoxil, amoxicillin, bacampicillin, benzylpenicillinic acid, benzylpenicillin sodium, epicillin, fenbenicillin, floxacillin, penamccillin, penethamate hydriodide, penicillin o benethamine, penicillin 0, penicillin V, penicillin V benzathine, penicillin V 25 hydrabamine, penimepicycline, and phencihicillin potassium), lincosamides (e.g., clindamycin, and lincomycin), amphomycin, bacitracin, capreomycin, colistin, enduracidin, enviomycin, tetracyclines (e.g., apicycline, chlortetracycline, clomocycline, and demeclocycline), 2,4-diaminopyrimidines (e.g., brodimoprim), nitrofurans (e.g., furaltadone, and furazolium chloride), quinolones and analogs 30 thereof (e.g., cinoxacin,, clinafloxacin, flumequine, and grepagloxacin), sulfonamides (e.g., acetyl sulfamethoxypyrazine, benzylsulfamide, noprylsulfamide, phthalylsulfacetamide, sulfachrysoidine, and sulfacytine), sulfones (e.g., 38 WO 2011/094708 PCT/US2011/023220 diathymosulfone, glucosulfone sodium, and solasulfone), cycloserine, mupirocin and tuberin. The compounds of the invention can be formulated in combination with an antiemetic agent. Suitable antiemetic agents include, but are not limited to, 5 metoclopromide, domperidone, prochlorperazine, promethazine, chlorpromazine, trimethobenzamide, ondansetron, granisetron, hydroxyzine, acethylleucine monoethanolamine, alizapride, azasetron, benzquinamide, bietanautine, bromopride, buclizine, clebopride, cyclizine, dimenhydrinate, diphenidol, dolasetron, meclizine, methallatal, metopimazine, nabilone, oxyperndyl, pipamazine, scopolamine, sulpiride, 10 tetrahydrocannabinols, thiethylperazine, thioproperazine, tropisetron, and mixtures thereof. The compounds of the invention can be formulated or formulated in combination with an antidepressant. Suitable antidepressants include, but are not limited to, binedaline, caroxazone, citalopram, dimethazan, fencamine, indalpine, 15 indeloxazine hydrocholoride, nefopam, nomifensine, oxitriptan, oxypertine, paroxetine, sertraline, thiazesim, trazodone, benmoxine, iproclozide, iproniazid, isocarboxazid, nialamide, octamoxin, phenelzine, cotinine, rolicyprine, rolipram, maprotiline, metralindole, mianserin, mirtazepine, adinazolam, amitriptyline, amitriptylinoxide, amoxapine, butriptyline, clomipramine, demexiptiline, 20 desipramine, dibenzepin, dimetacrine, dothiepin, doxepin, fluacizine, imipramine, imipramine N-oxide, iprindole, lofepramine, melitracen, metapramine, nortriptyline, noxiptilin, opipramol, pizotyline, propizepine, protriptyline, quinupramine, tianeptine, trimipramine, adrafinil, benactyzine, bupropion, butacetin, dioxadrol, duloxetine, etoperidone, febarbamate, femoxetine, fenpentadiol, fluoxetine, fluvoxamine, 25 hematoporphyrin, hypericin, levophacetoperane, medifoxamine, milnacipran, minaprine, moclobemide, nefazodone, oxaflozane, piberaline, prolintane, pyrisuccideanol, ritanserin, roxindole, rubidium chloride, sulpiride, tandospirone, thozalinone, tofenacin, toloxatone, tranylcypromine, L-tryptophan, venlafaxine, viloxazine, and zimeldine. 30 The compounds of the invention can be fonmulated in combination with an antifungal agent. Suitable antifungal agents include but are not limited to amphotericin B, itraconazole, ketoconazole, fluconazole, intrathecal, flucytosine, miconazole, butoconazole, clotrimazole, nystatin, terconazole, tioconazole, 39 WO 2011/094708 PCT/US2011/023220 ciclopirox, econazole, haloprogrin, naftifine, terbinafine, undecylenate, and griseofuldin. The compounds of the invention can be formulated in combination with an anti-inflammatory agent. Useful anti-inflammatory agents include, but are not limited 5 to, non-steroidal anti-inflammatory drugs such as salicylic acid, acetylsalicylic acid, methyl salicylate, diflunisal, salsalate, olsalazine, sulfasalazine, acetaminophen, indomethacin, sulindac, etodolac, mefenamic acid, meclofenamate sodium, tolmetin, ketorolac, dichlofenac, ibuprofen, naproxen, naproxen sodium, fenoprofen, ketoprofen, flurbinprofen, oxaprozin, piroxicam, meloxicam, ampiroxicam, droxicam, 10 pivoxicam, tenoxicam, nabumetome, phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine, apazone and nimesulide; leukotriene antagonists including, but not limited to, zileuton, aurothioglucose, gold sodium thiomalate and auranofin; steroids including, but not limited to, alclometasone diproprionate, amcinonide, beclomethasone dipropionate, betametasone, betamethasone benzoate, betamethasone 15 diproprionate, betamethasone sodium phosphate, betamethasone valerate, clobetasol proprionate, clocortolone pivalate, hydrocortisone, hydrocortisone derivatives, desonide, desoximatasone, dexamethasone, flunisolide, flucoxinolide, flurandrenolide, halcinocide, medrysone, methylprednisolone, methprednisolone acetate, methylprednisolone sodium succinate, mometasone furoate, paramethasone 20 acetate, prednisolone, prednisolone acetate, prednisolone sodium phosphate, prednisolone tebuatate, prednisone, triamcinolone, triamcinolone acetonide, triamcinolone diacetate, and triamcinolone hexacetonide; and other anti-inflammatory agents including, but not limited to, methotrexate, colchicine, allopurinol, probenecid, sulfinpyrazone and benzbromarone. 25 The compounds of the invention can be formulated in combination with another antiviral agent. Useful antiviral agents include, but are not limited to, protease inhibitors, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors and nucleoside analogs. The antiviral agents include but are not limited to zidovudine, acyclovir, gangcyclovir, vidarabine, idoxuridine, 30 trifluridine, and ribavirin, as well as foscarnet, amantadine, rimantadine, saquinavir, indinavir, amprenavir, lopinavir, ritonavir, alpha-interferons; adefovir, clevadine, entecavir, pleconaril. 40 WO 2011/094708 PCT/US2011/023220 The compounds of the invention can be formulated in combination with an immunomodulatory agent. Immunomodulatory agents include, but are not limited to, methothrexate, leflunomide, cyclophosphamide, cyclosporine A, mycophenolate mofetil, rapamycin (sirolimus), mizoribine, deoxyspergualin, brequinar, 5 malononitriloamindes (e.g., leflunamide), T cell receptor modulators, and cytokine receptor modulators, peptide mimetics, and antibodies (e.g., human, humanized, chimeric, monoclonal, polyclonal, Fvs, ScFvs, Fab or F(ab)2 fragments or epitope binding fragments), nucleic acid molecules (e.g., antisense nucleic acid molecules and triple helices), small molecules, organic compounds, and inorganic compounds. 10 Examples of T cell receptor modulators include, but are not limited to, anti-T cell receptor antibodies (e.g., anti-CD4 antibodies (e.g., cM-T412 (Boeringer), IDEC CE9.1* (IDEC and SKB), mAB 4162W94, Orthoclone and OKTcdr4a (Janssen Cilag)), anti-CD3 antibodies (e.g., Nuvion (Product Design Labs), OKT3 (Johnson & Johnson), or Rituxan (IDEC)), anti-CD5 antibodies (e.g., an anti-CD5 ricin-linked 15 immunoconjugate), anti-CD7 antibodies (e.g., CHH-380 (Novartis)), anti-CD8 antibodies, anti-CD40 ligand monoclonal antibodies (e.g., IDEC-131 (IDEC)), anti CD52 antibodies (e.g., CAMPATH 1H (Ilex)), anti-CD2 antibodies, anti-CD 11 a antibodies (e.g., Xanelim (Genentech)), and anti-B7 antibodies (e.g., IDEC-1 14 (IDEC)) and CTLA4-immunoglobulin. Examples of cytokine receptor modulators 20 include, but are not limited to, soluble cytokine receptors (e.g., the extracellular domain of a TNF-alpha. receptor or a fragment thereof, the extracellular domain of an IL-1.beta. receptor or a fragment thereof, and the extracellular domain of an IL-6 receptor or a fragment thereof), cytokines or fragments thereof (e.g., interleukin (IL) 2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-15, TNF-alpha., 25 interferon (IFN)-alpha., IFN-beta., IFN-gamma, and GM-CSF), anti-cytokine receptor antibodies (e.g., anti-IFN receptor antibodies, anti-IL-2 receptor antibodies (e.g., Zenapax (Protein Design Labs)), anti-IL-4 receptor antibodies, anti-IL-6 receptor antibodies, anti-IL-10 receptor antibodies, and anti-IL-12 receptor antibodies), anti cytokine antibodies (e.g., anti-IFN antibodies, anti-TNF-alpha. antibodies, anti-IL 30 beta antibodies, anti-IL-6 antibodies, anti-IL-8 antibodies (e.g., ABX-IL-8 (Abgenix)), and anti-IL-12 antibodies). The compounds of the invention can be formulated in combination with cytokines. Examples of cytokines include, but are not limited to, interleukin-2 (IL-2), 41 WO 2011/094708 PCT/US2011/023220 interleukin-3 (IL-3), interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-6 (IL-6), interleukin-7 (IL-7), interleukin-9 (IL-9), interleukin- 10 (IL- 10), interleukin- 12 (IL 12), interleukin 15 (IL-15), interleukin 18 (IL-18), platelet derived growth factor (PDGF), erythropoietin (Epo), epidermal growth factor (EGF), fibroblast growth 5 factor (FGF), granulocyte macrophage stimulating factor (GM-CSF), granulocyte colony stimulating factor (G-CSF), macrophage colony stimulating factor (M-CSF), prolactin, and interferon (IFN), e.g., IFN-alpha, and IFN-gamma). The compounds of the invention can be formulated in combination with hormones. Examples of hormones include, but are not limited to, luteinizing hormone 10 releasing hormone (LHRH), growth hormone (GH), growth hormone releasing hormone, ACTH, somatostatin, somatotropin, somatomedin, parathyroid hormone, hypothalamic releasing factors, insulin, glucagon, enkephalins, vasopressin, calcitonin, heparin, low molecular weight heparins, heparinoids, synthetic and natural opioids, insulin thyroid stimulating hormones, and endorphins. 15 The compounds of the invention can be formulated in combination with beta interferons which include, but are not limited to, interferon beta-i a and interferon beta-lb. The compounds of the invention can be formulated in combination with an absorption enhancer, particularly those which target the lymphatic system, including, 20 but not limited to sodium glycocholate; sodium caprate; N-lauryl--D maltopyranoside; EDTA; mixed micelle; and those reported in Muranishi Crit. Rev. Ther. Drug Carrier Syst., 7-1-33, which is hereby incorporated by reference in its entirety. Other known absorption enhancers can also be used. Thus, the invention also encompasses a pharmaceutical composition comprising one or more sulfated 25 polysaccharides of the invention and one or more absorption enhancers. The additional therapeutic agent can act additively or, more preferably, synergistically. In a preferred embodiment, a composition comprising a compound of the invention is administered concurrently with the administration of another therapeutic agent, which can be part of the same composition or in a different 30 composition from that comprising the compounds of the invention. In another embodiment, a compound of the invention is administered prior to or subsequent to administration of another therapeutic agent. In a separate embodiment, a compound of 42 WO 2011/094708 PCT/US2011/023220 the invention is administered to a patient who has not previously undergone or is not currently undergoing treatment with another therapeutic agent, particularly an antiviral agent. 5 Oral Dosage Forms A compound of the invention or a pharmaceutically acceptable salt, solvate or hydrate thereof and compositions comprising a compound of the invention that are suitable for oral administration can be presented as discrete dosage forms, such as, but are not limited to, tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g., 10 flavored syrups). Such dosage forms contain predetermined amounts of active ingredients, and may be prepared by methods of pharmacy well known to those skilled in the art. See generally, Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton Pa. (1990). Typical oral dosage forms of the invention are prepared by combining the 15 active ingredient(s) in an intimate admixture with at least one excipient according to conventional pharmaceutical compounding techniques. Excipients can take a wide variety of forms depending on the form of preparation desired for administration. For example, excipients suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and 20 coloring agents. Examples of excipients suitable for use in solid oral dosage forms (e.g., powders, tablets, capsules, and caplets) include, but are not limited to, starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents. Because of their ease of administration, tablets and capsules represent the most 25 advantageous oral dosage unit forms, in which case solid excipients are employed. If desired, tablets can be coated by standard aqueous or nonaqueous techniques. Such dosage forms can be prepared by any of the methods of pharmacy. In general, pharmaceutical compositions and dosage forms are prepared by uniformly and intimately admixing the active ingredients with liquid carriers, finely divided solid 30 carriers, or both, and then shaping the product into the desired presentation if necessary. 43 WO 2011/094708 PCT/US2011/023220 For example, a tablet can be prepared by compression or molding. Compressed tablets can be prepared by compressing in a suitable machine the active ingredients in a free-flowing form such as powder or granules, optionally mixed with an excipient. Molded tablets can be made by molding in a suitable machine a 5 mixture of the powdered compound moistened with an inert liquid diluent. Examples of excipients that can be used in oral dosage forms of the invention include, but are not limited to, binders, fillers, disintegrants, and lubricants. Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic 10 gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose, (e.g., nos. 2208, 2906, 2910), microcrystalline cellulose, and mixtures 15 thereof. Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures 20 thereof. The binder or filler in pharmaceutical compositions of the invention is typically present in from about 50 to about 99 weight percent of the pharmaceutical composition or dosage form. Suitable forms of microcrystalline cellulose include, but are not limited to, the materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICEL RC-581, AVICEL 25 PH-105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, Pa.), and mixtures thereof. A specific binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose sold as AVICEL RC 581. Suitable anhydrous or low moisture excipients or additives include AVICEL-PH 103.TM and Starch 1500 LM. 30 Disintegrants are used in the compositions of the invention to provide tablets that disintegrate when exposed to an aqueous environment. Tablets that contain too much disintegrant may disintegrate in storage, while those that contain too little may 44 WO 2011/094708 PCT/US2011/023220 not disintegrate at a desired rate or under the desired conditions. Thus, a sufficient amount of disintegrant that is neither too much nor too little to detrimentally alter the release of the active ingredients should be used to form solid oral dosage forms of the invention. The amount of disintegrant used varies based upon the type of formulation, 5 and is readily discernible to those of ordinary skill in the art. Typical pharmaceutical compositions comprise from about 0.5 to about 15 weight percent of disintegrant, specifically from about 1 to about 5 weight percent of disintegrant. Disintegrants that can be used in pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar-agar, alginic acid, calcium 10 carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof. Lubricants that can be used in pharmaceutical compositions and dosage forms of the invention include, but are not limited to, calcium stearate, magnesium stearate, 15 mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, tale, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof. Additional lubricants include, for example, a syloid silica gel (AEROSIL 200, manufactured by 20 W. R. Grace Co. of Baltimore, Md.), a coagulated aerosol of synthetic silica (marketed by Degussa Co. of Plano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, Mass.), and mixtures thereof. If used at all, lubricants are typically used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms into which they are incorporated. 25 Parenteral and Intravascular Dosage Forms Parenteral and intravascular dosage forms can be administered to patients by various routes including, but not limited to, subcutaneous, intravenous (including bolus injection and constant infusion), intramuscular, and intraarterial. Because their 30 administration typically bypasses patients' natural defenses against contaminants, parenteral and intravascular dosage forms are preferably sterile or capable of being sterilized prior to administration to a patient. Examples of parenteral dosage forms 45 WO 2011/094708 PCT/US2011/023220 include, but are not limited to, solutions ready for injection, dry products (including, but not limited to lyophilized powders, pellets, and tablets) ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions. 5 Suitable vehicles that can be used to provide parenteral dosage forms of the invention are well known to those skilled in the art. Examples include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles 10 such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate. Compounds that increase the solubility of one or more of the active ingredients disclosed herein can also be incorporated into the parenteral dosage forms 15 of the invention. For intravascular administration, for instance by direct injection into the blood vessel, or surrounding area, it may be desirable to administer the compositions locally to the area in need of treatment. This can be achieved, for example, by local infusion during surgery, by injection, by means of a catheter, or by means of an implant, said 20 implant being of a porous, non-porous, or gelatinous material, including membranes, such as silastic membranes, or fibers. A suitable such membrane is Gliadel@ provided by Guilford Pharmaceuticals Inc. Transdermal, Topical, And Mucosal Dosage Forms 25 Transdermal, topical, and mucosal dosage forms of the invention include, but are not limited to, ophthalmic solutions, sprays, aerosols, creams, lotions, ointments, gels, solutions, emulsions, suspensions, or other forms known to one of skill in the art. See, e.g., Remington's Pharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton Pa. (1980 & 1990); and Introduction to Pharmaceutical Dosage Forms, 4th ed., 30 Lea & Febiger, Philadelphia (1985). Dosage forms suitable for treating mucosal tissues within the oral cavity can be formulated as mouthwashes or as oral gels. Further, transdermal dosage forms include "reservoir type" or "matrix type" patches, 46 WO 2011/094708 PCT/US2011/023220 which can be applied to the skin and worn for a specific period of time to permit the penetration of a desired amount of active ingredients. Suitable excipients (e.g., carriers and diluents) and other materials that can be used to provide transdermal, topical, and mucosal dosage forms encompassed by this 5 invention are well known to those skilled in the pharmaceutical arts, and depend on the particular tissue to which a given pharmaceutical composition or dosage form will be applied. With that fact in mind, typical excipients include, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butane- 1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof to form lotions, 10 tinctures, creams, emulsions, gels or ointments, which are non-toxic and pharmaceutically acceptable. Moisturizers or humectants can also be added to pharmaceutical compositions and dosage forms if desired. Examples of such additional ingredients are well known in the art. See, e.g., Remington's Pharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton Pa. (1980 & 15 1990). Depending on the specific tissue to be treated, additional components may be used prior to, in conjunction with, or subsequent to treatment with active ingredient of the invention. For example, penetration enhancers can be used to assist in delivering the active ingredients to the tissue. Suitable penetration enhancers include, but are not 20 limited to: acetone; various alcohols such as ethanol, oleyl, and tetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethyl acetamide; dimethyl formamide; polyethylene glycol; pyrrolidones such as polyvinylpyrrolidone; Kollidon grades (Povidone, Polyvidone); urea; and various water-soluble or insoluble sugar esters such as Tween 80 (polysorbate 80) and Span 60 (sorbitan monostearate). 25 The pH of a pharmaceutical composition or dosage form, or of the tissue to which the pharmaceutical composition or dosage form is applied, may also be adjusted to improve delivery of one or more active ingredients. Similarly, the polarity of a solvent carrier, its ionic strength, or tonicity can be adjusted to improve delivery. Compounds such as stearates can also be added to pharmaceutical compositions or 30 dosage forms to advantageously alter the hydrophilicity or lipophilicity of one or more active ingredients so as to improve delivery. In this regard, stearates can serve as a lipid vehicle for the formulation, as an emulsifying agent or surfactant, and as a delivery-enhancing or penetration-enhancing agent. Different salts, hydrates or 47 WO 2011/094708 PCT/US2011/023220 solvates of the active ingredients can be used to further adjust the properties of the resulting composition. Although methods and materials similar or equivalent to those described herein can be used in the practice of the present invention, preferred methods and 5 materials are described below. The materials, methods, and examples are illustrative only and not intended to be limiting. Other features and advantages of the invention will be apparent from the detailed description and from the claims. Kits 10 This invention therefore encompasses kits which, when used by the medical practitioner, can simplify the identification of subjects and the administration of appropriate amounts of a compound of the invention or a pharmaceutically acceptable salt, solvate or hydrate thereof to a patient. A typical kit of the invention comprises one or more unit dosage forms of a 15 compound of the invention or a pharmaceutically acceptable salt, solvate or hydrate thereof, and instructions for identification of a subject. Kits of the invention can further comprise devices that are used to administer a compound of the invention or a pharmaceutically acceptable salt, solvate or hydrate thereof. Examples of such devices include, but are not limited to, intravenous 20 cannulation devices, syringes, drip bags, patches, topical gels, pumps, containers that provide protection from photodegradation, autoinjectors, and inhalers. Kits of the invention can further comprise pharmaceutically acceptable vehicles that can be used to administer one or more active ingredients. For example, if an active ingredient is provided in a solid form that must be reconstituted for 25 parenteral administration, the kit can comprise a sealed container of a suitable vehicle in which the active ingredient can be dissolved to form a particulate-free sterile solution that is suitable for parenteral administration. Examples of pharmaceutically acceptable vehicles include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, 30 Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but 48 WO 2011/094708 PCT/US2011/023220 not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate. All documents mentioned herein are incorporated herein by reference in their entirety. 5 EXAMPLES In order that the invention may be more fully understood, the following examples are provided. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting the invention in any 10 way. General Experimental Methodology 1. To identify potent and selective small molecule modulators of MCL-1, a small molecule binding screen by competitive fluorescence polarization assay was conducted. Small molecules were screened in parallel against the FITC-MCL 15 1 SAHB/MCL-lANAC interaction and the FITC-BAD BH3/BCL-XLAC interaction. Those compounds that preferentially disrupted the FITC-MCL-1 SAHB/MCL-lANAC interaction were advanced to secondary screening analyses. 20 2. A series of confirmatory binding assays were performed. First, the competitive binding assay using FITC-MCL-1 SAHB/MCL-lANAC was repeated using dose-response analysis to confirm dose-responsive binding and determine small molecule Ki values. Subsequently specificity analysis was performed by competitive fluorescence polarization binding assay of small molecules 25 against the interactions of FITC-BID BH3 in combination with MCL-lANAC, BCL-2AC, BCL-XLAC, BCL-wAC, and BFL1/A1AC. Small molecules exhibiting high fidelity specificity for MCL-lANAC over the other anti apoptotic proteins were advanced to SAR, binding site, and functiolial analysis. Docking analysis was performed to confirm the compatibility of 30 small molecule structure with an energetically favorable docking site at the structurally defined (i.e. x-ray crystallography) BH3-binding pocket of MCL 1ANAC. Dilutional assays were performed to distinguish between non 49 WO 2011/094708 PCT/US2011/023220 covalent and covalent MCL-1 binders. These studies identified a series of covalent interactors; for example, a novel site of interaction for inhibiting MCL-1 binding activity was identified based on covalent modification of MCL-1 by the molecule at cysteine 286. Finally, selective MCL-1 inhibitors 5 were tested in a BAX-mediated liposomal release assay to evaluate their capacity to block the inhibitory/anti-apoptotic activity of MCL-1. 3. Small molecule modulators of MCL-1 were then tested in a cellular apoptosis sensitization assay using OPM2 cells exposed to subcytotoxic doses of TRAIL 10 in the presence or absence of serial dilutions of small molecule. Sensitization activity was also confirmed by use of CalcuSyn analysis of combination treatments. 15 Methods SAHB Synthesis. Hydrocarbon-stapled peptides corresponding to BCL-2 family BH3 domains and their FITC-PAla derivatives were synthesized, purified, and characterized using previously described methodologies 24 27
,
29 20 Anti-apoptotic protein preparation. Recombinant and tagless MCL-lANAC, BCL 2 AC, BCL-XLAC, BCL-wAC, and BFLl/AlAC were produced using previously described methods 27 29 31 25 Small molecule screening. Small molecule screens were performed at the Institute for Chemistry and Cellular Biology at Harvard Medical School and employed commercial libraries (Asinex, Chembridge, ChemDiv, Enamine, Life Chemicals, and Maybridge). A high-throughput competitive FP binding assay was employed to screen for small molecules that disrupted the interaction between FITC-MCL-1 30 SAHB (15 nM) and MCL-lANAC (45 nM). MCL-lANAC was expressed and purified by FPLC and delivered by automated liquid handler to 384 well plates, followed by addition of small molecule libraries. After a 15 minute incubation at room temperature, FITC-MCL-1 SAHB (15 nM) was added to each well by liquid 50 WO 2011/094708 PCT/US2011/023220 handler and FP read at equilibrium (e.g. 1 hr). Small molecule hits were re-examined in this assay using serial dilutions of the compounds to confirm dose-responsive inhibition of FITC-MCL-1 SAHB binding. 5 Confirmatory binding analyses. The most potent hits were advanced to rigorous quantification of binding activity and specificity. First, serial dilutions of small molecule in triplicate were mixed with FITC-MCL-1 SAHB (15 nM), followed by addition to 384-well black Costar plates containing MCL-1ANAC (45 nM) diluted in binding buffer (50 mM Tris, 100 mM NaCl, 0.0625% CHAPS, pH 8.0). The plates 10 were incubated in the dark at room temp until equilibrium was reached (i.e. stabilization of binding isotherms) and FP (mP units) determined using a microplate reader (e.g. Spectramax). K values were calculated by nonlinear regression analysis of dose-response curves using Prism software (Graphpad). Small molecule hits were then tested for their ability to dissociate FITC-BAK BH3 from MCL-lANAC in a 15 competitive FP assay, performed as described above except that small molecule dilutions' were added to a solution of FITC-BAK BH3 (25 nM) and MCL-1ANAC (250 nM) to simulate a physiologic displacement of pro-apoptotic BAK from the inhibitory MCL-1 protein. For rigorous specificity analysis, the identical competitive FP-type experiment was performed except that serial dilutions of small molecule hits 20 were mixed with the pan-anti-apoptotic binder FITC-BID BH3 (15 nM), followed by addition to plates containing either MCL-1ANAC, BCL-2AC, BCL-XLAC, BCL wAC, or BFL1/A1AC. We used pGEX vectors to express GST-MCL-1ANAC, BCL 2AC, BCL-XLAC, BCL-wAC, and BFL1/A1AC, followed by thrombin cleavage and FPLC-based gel filtration chromatography. Of note, the C-terminal alpha-helix was 25 deleted from each of these constructs to facilitate protein expression and purification; an additional N-terminal deletion of MCL-1 was performed to further enhance expression, purity, and stability. FP analysis was performed as above and those molecules showing exclusive binding activity for MCL-1ANAC were .advanced to structural docking and functional testing. 30 Dilution assay. MCL-1ANAC (2 ptM, 500 mL) was incubated with compound (at a ratio well above each previously determined EC 50 value) for 1 hour at room temperature in FP buffer (100 mM NaCl, 50 nM Tris, pH 8). A small sample was taken as a pre-dilution control. Compound-treated protein and unmodified protein 51 WO 2011/094708 PCT/US2011/023220 were then diluted to a volume of 20 mL, and subsequently re-concentrated to 500 mL using 10K centrifugal filter units (Amicon). FP binding analysis was performed as described above by adding serial dilutions of compound-modified MCL-1 and unmodified MCL-1, both before and after dilution, followed by FITC-BID BH3 (15 5 nM) to a 96-well black flat bottom plate (Costar). FP measurements and analyses are then performed as described above. Identification of covalent modification site by mass spectrometry. MCL-1ANAC (90 p.M) was incubated with a 1:1.25 ratio of compound for 2 hours at room 10 temperature in 150 mM NaCl, 50 mM Tris, pH 7.4. Excess compound was removed by gel filtration and the protein was digested with trypsin overnight at 37 *C. Peptides were analyzed by nano-LC/ESI/MS using a vented column assembly as described (Ficarro et al., 2009)34. Briefly, peptides were injected using an autosampler and HPLC (Waters NanoAcquity) onto a self-packed precolumn (4 cm, 100 pm I.D., 15 POROS1OR2, Applied Biosystems) and gradient eluted (0-30% B in 20 minutes, A=0.2 M acetic acid in water, B=acetonitrile with 0.2M acetic acid) to the resolving column (self-packed 30 pm I.D., 12 cm of 5 pm Monitor C18, Column Engineering) and introduced to the mass spectrometer (Thermo Fisher LTQ-Orbitrap XL) via ESI (spray voltage = 2.2 kV). The top 8 most abundant precursors in each MS scan 20 (image current detection, resolution = 30,000) were subjected to CAD (electron multiplier detection, collision energy=35%). A separate targeted nano-LC/ESI/MS experiment was performed with compound-modified peptide (e.g. TINQES*CIEPLAESITDVLVR [*C= modified cysteine)]), which was subjected to HCD (higher energy collisionally activated dissociation). 25 Liposomal release assay. Liposomes are prepared from a mixture of lipids that reflect the composition of the outer mitochondrial membrane as previously described in detail (Pitter et al., 2008)31. Aliquots of mixed lipids (1 mg total) are stored in glass at -20'C under nitrogen, and before use, resuspended in liposome assay buffer (10 30 mM HEPES, 200 mM KCl, 1 MM MgCl 2 , pH 7) with 12.5 mM of the fluorescent dye ANTS (8-aminonaphthalene-1,3,6-trisulfonic acid, disodium salt) and 45 mM of the quencher DPX (p-xylene-bis-pyridinium bromide). The resulting slurry is vortexed for 10 minutes and freeze-thawed five times alternating between liquid nitrogen and a 52 WO 2011/094708 PCT/US2011/023220 40'C water bath. The solution is then passed through an Avanti Mini-Extruder Set (#610000) equipped with a 100-nm filter, followed by passage through a Sepharose column (GE Healthcare) to remove residual ANTS/DPX. The lipsomes are brought up to a volume of 3 mL to produce a final liposome stock. For the liposomal release 5 assay, a total volume of 30 piL is used in 384 well black flat bottom plates (Costar), and baseline fluorescence measurements of 8 tL liposomes are made for 10 minutes using the Tecan Infinite M1000 (excitation: 355 rn, emission: 520 un). Following the baseline read, recombinant MCL-1ANAC pre-incubated with a 1:1 ratio of compound is added to the liposomes. Next, 20 nM caspase-cleaved mouse BID (R&D 10 systems) and 250 nM purified recombinant monomeric BAX is added, and fluorescence measurements (F) are recorded every minute from time zero (FO) until the release readings plateau. The liposomes are then quenched with 1% Triton X-100 (100% release; F100), and percent ANTS/DPX release is calculated as ((F FO)/(F 100 - FO)) x 100. 15 Cytochrome c Release Assays. Mouse liver mitochondria (0.5 mg/mL) are isolated and release assays performed as described. Mitochondria are incubated with a serial dilution of MCL-1 targeting small molecule, singly or in combination with BID BH3, and after 40 minutes, the pellet and supernatant fractions are isolated and cytochrome 20 c quantitated using a colorimetric ELISA assay (R&D Systems). Percent cytochrome c released into the supernatant (%cytocup) from releasable mitochondrial pools was calculated according to the following equation: %cytoc=[(cytocup cytOcbackgr)/(cytoctotal-cytoCbacky)] * 100, where background release represents cytochrome c detected in the supernatant of vehicle-treated (1% DMSO) samples and 25 total release represents cytochrome c measured in 1% Triton-X 100 treated samples. All experimental conditions are also tested on Bak"- mitochondria to ensure that the observed cytochrome c release from wild-type mitochondria derives from BAK activation. 30 Immunoprecipitation Assay. MCL-1-expressing cancer cells (10 x 106) are incubated with the MCL- 1 targeting small molecule or vehicle in serum-free media at 37"C for 4 hours, followed by serum replacement for an additional 6 hours. After cellular lysis in 50 mM Tris (pH 7.4), 150 mM NaCl, 1 mM EDTA, 1 mM DTT, 0.5% NP40 and complete protease inhibitor pellet, cellular debris is pelleted at 14,000 g for BoS2 839804. 1 53 WO 2011/094708 PCT/US2011/023220 10 minutes at 4*C. The supernatant is exposed to pre-equilibrated protein A/G sepharose beads and the pre-cleared supernatant subsequently incubated with anti MCL-1 antibody for 1.5 hours at 4"C, followed by the addition of protein A/G sepharose beads for 1 hour. The beads are pelleted and washed with lysis buffer for 5 10 minutes at 4 0 C. The washed bead are then pelleted, heated to 90*C for 10 minutes in SDS loading buffer, analyzed by SDS/PAGE, and then immunoblotted for MCL-1 and BAK. Crystallography. Crystallization conditions for lead small molecule-MCL-1ANAC 10 complexes are screened using 96-well sitting drop plates set up using a Phoenix crystallization robot. Initial conditions include HT Index Screen, JSCG+ Suite, and Pro-Complex Suite. Screening around the best hit, including varying pH, salt, and detergent concentrations, are performed to identify the best condition for crystal growth. Once generated, the crystals are removed, washed in the crystallization 15 buffer, and subjected to mass spectroscopy to verify the presence of compound and protein within the crystal. The crystal is then soaked in cyroprotectant, flash frozen, and stored in liquid nitrogen. Suitable crystals are examined at the Argonne National Laboratory synchrotron facility. Phases are obtained by molecular replacement followed by data analysis and refinement (Phaser, Phenix, and Coots software). 20 Cellular apoptosis induction assays. Small molecule inhibitors of MCL-1 were screened in MCL-1-expressing cancer cell lines, such as OPM-2 (multiple myeloma) cells. The cells are treated with the small molecule MCL-1 inhibitor, alone or in combination with subtherapeutic pro-apoptotic stimuli (e.g. TRAIL, Fas ligand, ABT 25 737), and then cell viability is measured at 48 hours by MTT assay performed according to the manufacturer's protocol (Roche) and quantitated by an ELISA microplate reader (Biorad). IC 50 values were determined by nonlinear regression analysis using Prism software (Graphpad). Small molecules that decrease cell viability are then screened for cellular apoptosis induction by annexin V binding and 30 FACS analysis, and by cell fractionation-based mitochondrial cytochrome c release, as described 28 . Apoptosis is also correlated with in situ dissociation of the MCL 1/BAK complex (immunoprecipitation) performed as described above. As an additional measure of small molecule MCL-1 specificity, the identical experiments are conducted on wild-type vs. Mcl-T' MEFs, to explicitly link the selective MCL-1 54 WO 2011/094708 PCT/US2011/023220 targeting capacity of the small molecules to sensitization of apoptosis. The caspase dependency of small molecule activity is also confirmed by monitoring for blockade of activity upon co-treatment with the pan-capase inhibitor Z-VAD. 5 Pharmacokinetic analyses. Lead small molecules undergo pharmacokinetic (PK) analysis in mice, performed in conjunction with the DF/HCC Clinical Pharmacology Core. LC/MS-based analytical assays are developed in order to detect and quantify compound levels in plasma. For PK analysis, small molecules (e.g. 10, 50, 100 mg/kg) are injected by tail vein or intraperitoneally into male C57/BL6 mice. Blood 10 samples are withdrawn by retro-orbital bleed at various time points and plasma isolated for compound quantification, followed by calculation of plasma half-life, peak plasma levels, total plasma clearance, and apparent volume of distribution. Small molecules that exhibit selective MCL-1 targeting in cells and exhibit a favorable pharmacokinetic profile re advanced to in vivo testing. 15 In vivo efficacy studies. Small molecule-sensitive cancer cell lines are retrovirally transduced to achieve stable luciferase expression (pMMIP-LucNeo) and transplanted into SCID beige mice as previously described. Initial xenograft studies examine 5 mouse cohorts (n=10), treated with either vehicle alone, low or high dose small 20 molecule alone, or low/high dose small molecule in combination with subtherapeutic dosing of pro-apoptotic stimuli (e.g. TRAIL, ABT-737, doxorubicin, etoposide, dexamethasone). Starting on experimental day 1, mice receive a once daily tail injection of small molecule (e.g. 25 or 100 mg/kg, with or without combination treatment). For alternate day in vivo tumor imaging, mice are anesthetized with 25 inhaled isoflurane and treated concomitantly with intraperitoneal injection of D luciferin. Photonic emission is imaged (2 min exposure) using a Xenogen In Vivo Imaging System and total body bioluminescence quantified by the integration of photonic flux (photons/sec) using Xenogen's Living Image Software. The survival distributions of experimental mice are determined using the Kaplan-Meier method 30 and compared using the log-rank test. The Fisher's exact test is used to compare the proportion of mice who fail treatment, where treatment failure is defined as progression or death, and success as stable disease or regression. If a treatment response is observed with a particular small molecule, three additional cohorts, treated with either vehicle, small molecule, or small molecule combination will be used for 55 WO 2011/094708 PCT/US2011/023220 pharmacodynamic studies in which pro-apoptotic activity is evaluated in tissues by TUNEL and activated caspase-3 immunohistochemical staining. 5 Examples: Identification of MCL-1 selective small molecules by a competitive fluorescence polarization binding assay using FITC-MCL-1 SAHB and MCL-1ANAC. A 10 high-throughput competitive FP binding assay was employed to screen for small molecules that disrupted the interactions between FITC-MCL-1 SAHB/MCL-1ANAC and FITC-BAD BH3/BCL-XLAC (Figure 1). Compounds were ranked based upon their selectivity for MCL-1ANAC over BCL-XLAC targeting, and tabulated (see Table 1 (including Subtables Table 1-A through Table 1-P)). 15 The structures of small molecule/MCL-1 complexes provide a template for refining MCL-1 binding activity and specificity. Using the crystal structure of MCL-lANAC, the identified small molecules were docked onto the BH3-binding pocket of MCL-1ANAC to analyze the location and energetic favorability of 20 interaction. The compounds covered discrete subregions of BH3-binding pocket topography (Figure 2), providing a blueprint for engineering selective, larger molecules that incorporate combinations of molecules or their subfragments to engage the complex and extended BH3-binding surface of MCL-1. 25 Subclassification of selective MCL-1 inhibitors based on non-covalent vs. covalent interactions. To examine the mechanism of small molecule binding to MCL-1, the compounds were subjected to a rapid dilution assay (Figure 2C). Briefly, MCL-1ANAC was pre-incubated with the small molecule inhibitors prior to dilution with buffer. The solution was concentrated to its original volume and fluorescence 30 polarization was performed. Compounds that bind covalently will remain bound to the protein, whereas compounds that bind reversibly will be exchanged upon dilution. As a positive control, the rapid dilution assay confirmed that gossypol (1570G15) bound reversibly to MCL-lANAC (Figure 2C, top panel). In contrast, 1725P16 and 56 WO 2011/094708 PCT/US2011/023220 1597E07 failed to exchange upon dilution, indicating that the compounds bind and covalently modified MCL-1ANAC (Figure 2C, middle, bottom panels). Identification of a novel interaction site for MCL-1 inhibition based on C286 5 engagement. To localize sites of covalent modification, small molecule-treated MCL-lANAC (e.g. 1929A19) was subjected to mass spectrometry. An additional MALDI peak was observed for small molecule-treated protein, with the increase in mass corresponding to the molecular weight of the covalently tethered compound. The MCL-1ANAC-adduct was further subjected to tandem MS/MS, which revealed 10 cysteine 286 as the site of modification for 1929A19 (Figure 2D). Importantly, cysteine 286 is not located at the canonical BH3 binding pocket (Figure 2D), indicating that engagement of this novel binding site can allosterically regulate MCL l's anti-apoptotic/BH3-binding activity. To confirm the functional importance of C286 engagement, a C286S construct of MCL-lANAC was generated by site-direct 15 mutagenesis and small molecule binding activity was compared in competitive FP assays using FITC-BID BH3 and the wild-type and mutant MCL-1ANAC proteins. Whereas 1929A19 and 1616N08 competed with FITC-BID BH3 for MCL-1ANAC binding, the molecules failed to engage the C286S construct of MCL-1ANAC, as demonstrated by the capacity of FITC-BID BH3 to maintain binding activity toward 20 MCL-1ANAC C286S in the presence of the compounds. Confirmation of small molecule binding activity and selectivity by use of competitive binding assays. To verify the capacity of the identified small molecules to selectively target MCL-1ANAC, small molecule hits were tested for their 25 differential ability to dissociate FITC-BID BH3 from a panel of anti-apoptotic proteins, including MCL-1ANAC C, BCL-2AC, BCL-XLAC, BCL-wAC, and BFL1/A1AC. As exemplified in Figures 3 and 4, small molecules identified as MCL 1ANAC selective indeed exhibited preferential displacement of FITC-BID BH3 from MCL-1ANAC compared to the other anti-apoptotic proteins tested. 30 Structure-activity relationship analysis of selective MCL-1 inhibitors. Chemical derivatives of class A (figure 4C) and J (Figure 4D) molecules demonstrated significant differences in binding activity. Importantly, the five-member thiotriazole 57 WO 2011/094708 PCT/US2011/023220 ring at position R1 of class A increased binding affinity for MCL-1ANAC compared to smaller, non-aromatic substituents. At the R2 position, aromatic residues were favored with small hydrophobic side chains or hydrogen bond acceptors at the para position of the phenyl ring. For class J, small aliphatic groups were well tolerated at 5 the RI position, and the trihydroxyphenyl ring at the R2 position demonstrated superior binding affinity for MCL-1ANAC. Finally, five- or six-member aromatic rings were favored at the R3 position. Specifically, analogs that contained methyl substituents at R3 displayed no activity unless paired with a large aliphatic group at the R1 position. 10 Small molecule MCL-1 binders sensitize cancer cells to pro-apoptotic stimuli. Cancer cells that depend on MCL-1 for survival were treated with selective small molecule MCL-1ANAC binders in combination with other pro-apoptotic agents to assess for synergistic anti-tumor activity. As exemplified in Figure 5, small molecule 15 bioactives synergized with TRAIL to kill OPM2 multiple myeloma cells, as assessed by MTT viability assay and by combination treatment analysis using CalcuSyn software. Selective MCL-1 inhibitors block the anti-apoptotic function of MCL-1 in a 20 BAX-mediated liposomal release assay. The liposomal release assay is designed to mimic the functional release of mitochondrial cytochrome c by formation BAX containing pores within the outer mitochondrial. membrane. Here, recombinant full length BAX was incubated with recombinant tBID in the presence or absence of MCL-1ANAC. As demonstrated in figure 6, tBID triggered BAX-mediated release of 25 the fluorophore from the liposome in a time-dependent manner. MCL-1ANAC blocked BAX activation, inhibiting fluorophore release. By inhibiting MCL-lANAC, 1929A19 and 1616N08 dose-responsively re-instated tBID-induced, BAX-mediated liposomal release of the fluorophore, highlighting the capacity of the small molecule MCL-1 inhibitors to block the anti-apoptotic activity of MCL-1. 58 WO 2011/094708 PCT/US2011/023220 TABLE- 1-A ... ... 2 .4. b4~OHO HOH 34.13126897 102.3629331 68,231669 O OH OH63 O3LOO9 HO OH HO 0 OH OH 16.68871081 105.341600 1 oo o oou N 34.54623163 100.760843 66.214611 O OH H 35.01128141 106.8345939 71.823312 N CH. HIN H 56.60157162 106.2747212 49,67315 OH 0 OH OOH 10.32290702 104.1661092 93.843202 59 WO 2011/094708 PCT/US2011/023220 OH HO 0 0 0 OH OH 1.259544221 90.57802572 89.318482 o O 0 MH Na* 27.20036677 100.4228001 73.222433 10 - Pi-5700l5 NO OH -N 3.955080904 101.0243434 97.069262 cI OH Ho cC 41,01271009 100.3606236 59.347914 0 0 HO OH 32.90443509 97.09434568 64,189911 HH OH HO OH H O HO OH HO HO OH O O OH OH HO OOHHO HO OH 15.93536133 98.2573418 82.32198 60 WO 2011/094708 PCT/US2011/023220 TABLE 1-B R1 0 0 O N RI = heterocycle or aromatic R2 = H or S 0 heterdcycle or. aromatic H N N 2.332623997 103.4341651 101.1015411 FS N N N S 0 4,951710591. 96.11650485 91.16479426 HO 19.67020024 96.38730675 76.71710652 61 WO 2011/094708 PCT/US2011/023220 Hr N N SS N 0 19.74954984. 93.16376474 73.4142149 0 -NO S NNN 36.15465782 91.34577213 55.19111431 62 WO 2011/094708 PCT/US2011/023220 TABLE 1-C N OH N R1 N R2 where R3 heterocycle or aromatic N O,4 6 3 2 9 6 9 3 1 1 1 5 .1 8 4 8 2 3 3 : 1 0 5 . 7 2 1 5 2 7 4 ; OH N OH O HNN -0.3 1084 108.7 F N OH HN N HO 42.48636709 113.7228826 71,23651547 63 WO 2011/094708 PCT/US2011/023220 N :HO HN N', o 0 NI O OH 27.16644285 93.0177803 65.85133746 N OH OH -N 43.7012494 106.4064449 62.70719545 s N OH HN N 0 58.33277892 103.7511722 45.41839332 64 WO 2011/094708 PCT/US2011/023220 TABLE 1-D 0 N N N SR N N 0 N R .;:2EfSitrdotuye . .MOL1i%fBounid BCL-X15% Bounld S Sp~eas. ON 0O 0 14.6 . 101.3 .7 NH -2.04714193 75.96629122 78.01343315 -o0 HN-6 N 0P N / 8.332108744 81.17127433 72.B3916559 65 WO 2011/094708 PCT/US2011/023220 00 N NH QS 0 N-N 0 \\ 0 NK HN 0 35,72624681 99.74101397 64.01476715 N66 O0 N-NN 5* 0 cI s N NQ 46.37762426 98.52068172 53.14306746 66 WO 2011/094708 PCT/US201 1/023220 TABLE 1-E
R
2 RI 0 where RI amide or ester R2 =heterocycle or ................. aromatic ____ _____jd BG6L-XL% Brfi~ H ) N0 00 _____________________________________-0.73337205Ji 80.396769391 81.13014i45; NT N , 0 NH 0 ________ 11,_______________I 728005051 79.877899881 68.14989482! -Z . ______ _______________________ 38,47471452! 101.4501065 62.975399 67 WO 2011/094708 PCT/US201 1/023220 KB / H NH N 47.00574838! 9.5113873 52,245390351 0 0 00 0 Br NH ___________________________________47.953523241 96.903616331 48.95009309 68 WO 2011/094708 PCT/US2O1 1/023220 0/ 0 HN 'N N N 0I __________________________________ I56.33127545, 1014.4315992 48.1003237J1 N N K 055.14812663, 103.2306124,___ 48.082485771 eNH ___________________________________64.637660281 112.70478641 48.0671261 69 WO 2011/094708 PCT/US201 1/023220 N 0 _________________________________62.7184466 110.08256591 47,36411 9291 Is. N H 0_________ _________-__-_ _ _- 40.509958921 86.74650699 46.23654806 -NH 1 ____________________________________66.090538041 111.99991681 45.90937874F N Hb ____________________________________56.1 04283051 101 .7632641 45.658980961 70 WO 2011/094708 PCT/US201 1/023220 _____ _____________ _____ 69,534613541 115.19857431 45.66396079; oo~ ___________________________________68.796119161 114.18049371 45,38437457! 71 WO 2011/094708 PCT/US2011/023220 TABLE 1-F R2 N S N HN N N N N HN 0 S _ 14,30073607 84.68236855 70.38163248 0 N S N NHN 25,28012412 92.88964225 67.60951814 72 WO 2011/094708 PCT/US2011/023220 0 N N HN 0 0 19.17808219 73.82692962 54.64884742 O N' S N N ' N HN 0 CI 0 33.27874504i 82.61218664 49.33344159 73 WO 2011/094708 PCT/US2011/023220 TABLE 1-G 0 NC NH R1R S S R where RI heterocycle or aromatic Strucbture ' MCL 1 % Bound: BCL-XLP/% Boun~d Spec Values*~~ 0* N NH S S 0 24.59486004 99.32600497 74.73114493 N NH S S 0 1.§.96382387 92.90700473 73.94318087 N NH S S OH 15,16614831 84.81906443 69.65291612 74 WO 2011/094708 PCT/US2011/023220 0 N NH S s N 30.48780488 79.68386424 49.19605936 75 WO 2011/094708 PCT/US201 1/023220 TABLE 1-H NC 0 iN-R1 ",C : where RI= aromatIc R1 0 or heterocycle R2 = CH2 _______ _____________________________________ ____ ___ _____-1 a.5954323 7. 60 1__i97.757483751 N 17.0372618 97.35012677! 90.312861 61 _____ ___________ _____3.3686,7863! __,_6.24446993 82,8767913 76 WO 2011/094708 PCT/US201 1/023220 02 HO ________________________________________________________-7.07177814! 75.49565787 82,56743601! __________________________________________________20.588235291 102.1 918705i 81.60363516 OH _____- - -30.1 971050j___ 107.6879038 77.49079881 77 WO 2011/094708 PCT/US201 1/023220 NH, HO / N / 0 N ____________________________________________________21.81 98.2 76.4! HO N __________________________________HO_______ 15.044656611 89,367792691 74.323135981 ___ __________________________ 1.2014 8926945~5.87N36 y 78 WO 2011/094708 PCT/US201 1/023220 00 HOH 0 _________________________________________________________36.805768641 89.701322021 52.895653381 ______________________________________________ 3.204559.52373[5.7127N 0_________________________________________2.3706 87896 94321I 70 WO 2011/094708 PCT/US2011/023220 TABLE 1-I .R1 where R1 = H or 0 sulfonamide-, ester- or amide linked heterocycle R2 or aromatic R2= H or aromatic ci HO 0 Ci 0 -5.219264716 104.6841563, 109.903421 0 0 HO S 11.19902121 76.15107324 64.95205204 H S N ~ - 0 0 25.38058602 86.7447645 61.36417848 80 WO 2011/094708 PCT/US2011/023220 00 00 00 44.3557943 92,23836973 47.88257544. 81 WO 2011/094708 PCT/US201 1/023220 TABLE 1-J 0
R
3
N
7 0 N X R2 where X = S or 0. R3 = aromatic or heterocycle 0 NH - S N 0 /0 I - -.-------- .I19.08127201 95,0854353176.0041632 3 0 N NN _____43,51306119! 106.9095962 63.396535041 _____________________________________________________39.32183657 100.3628503 .6.4033 82 WO 2011/094708 PCT/US2011/023220 N 0 N HN 41.8167411 102.1683264 60.35158527 /0--\N ~ 0 Br O0 HN 0 N H 0 38.17542436 95.91685226 57.74142791 0 H 5.19897498 102.0166733 56.81769831 83 WO 2011/094708 PCT/US2011/023220 0Y N O 0 HO 0 HO_ __ 041.985733 98.20470972 56.21897672 S N Q N 0 52.01193335i 105.6743612 53.6624278 0s HN N O N 0 N S 46.42363385 99.00409172 52.58045787 HN 0 NH b/ 0 CIO 39,963529251 92.21643287 52.25290362 84 WO 2011/094708 PCT/US2011/023220 0 HN 0= N 0 SHO OH 30.59011861 81.34023006 50.75011146 0 S N 0 N HN 33.00999412 82.65729799 49.64730387 S N N O 0 S_51.188624751 99.22340759 48.03478284 N N 0 0 55.45434348 100.8550361 45.4006926 85 WO 2011/094708 PCT/US201 1/023220 TABLE 1-K 0
X-R
3 R2 where Rl phenyl or furan _____ _____ _____ _____ _____ _____ _____ _____ _____ ____ X =N or C-________ _____ -r- ~ ~ -- *- . ..~. . ~ . ~ .X~ZT S~~ ~ ~ . . . R-- ~ - 2.606828112! 96.58770003, 93.980871 92 IN 00 NH s ____________________________________ 15.57226143 89.4401828 73.867921371 .1________________________ NH 48.251651 11.214653 62.999487151 86 WO 2011/094708 PCT/US2011/023220 NH 0 0 0 43.163792481 101.2275149 58.063722391 HN N 0 H HN ________ __________ _____________________________48.95344507 97.58836088 48.63491 581 0 HN 01.60215433 6.7537406 48.135286273 N 00 S 0 HO 215.60154331 263.7374061 48.135862731 87 WO 2011/094708 PCT/US2011/023220 N 0. 0 HN N 40.421927931 87.79749734 47.37556941 88 WO 2011/094708 PCT/US2O1 11023220 TABLE 1-L
R
3 O N R2 where XI 0 or X2 S or N ........ ~ ... ~..' I3 Structure ULU- oud ________ Se au S, 0S N OH 0 0 ___ - 9.61778443 87.82745228i 97.43823.0721 * HN 5 0 N N 0<0 0 J40 0& NH ________________________19.68883273 - 102.40944241 82.726068 N Br 0 _____________________________ ____33.270292761. 112.3457833! 79.07540 89 WO 2011/094708 PCT/US2011/023220 S HO SO 0 N 0 26.07784431 102.76836631 76.69052194 S S N NH O HO _ _ _ _19.8 95._-_ _ 8i 76.1 0-0 NN 0 0 s NH 0 38.57217917 107.8998073, 69.327628151 S Ks N 0 00 0 or0 OH 21.287425151 90.20742087j 68.919995721 90 WO 2011/094708 PCT/US2011/023220 0 s 0 N 23.0 89.9 66.9 N N SN 0, 0 NH 0 __________ _______________ ~ 29.45492662 92.21 5568861 62.76064224 FS NH 0 38.04746419 93.34466638 55.29720219 91 WO 2011/094708 PCT/US2011/023220 N OH 1 21,54074074. 76.08572124i 54.5449805 S F o1 N 0F F F 42.5929832 94.16497422! 51.57199103 S ~39.83535868 91.733398041 51.89803936 0 N N o 48.7076967 98.89474361 50.1870469 92 WO 2011/094708 PCT/US2011/023220 0 NH2 0 SS N 58.508629991 105.8574397 47.34880968 93 WO 2011/094708 PCT/US2011/023220 TABLE 1- M R, R3 N where R1 = R aromatic or N2 heterocycle s HO N-N HO OH N -- 23.10049446 101.7468716 124.8473661 N HO S N-N HO OH -16.27483907 89.94614004 106.2209791 94 WO 2011/094708 PCT/US2011/023220 TABLE 1-N N N ON -65.83063646 102.6892674___168.5199038 0 O N H -6.59173964 129.3090909 1 35.9008305j Ho O -- N N -23.10049446 101.7468716 124.8473661 N N- 0 00 0 -30.96202705 88.78573776 119.7477648 cI HO H -5.219264716 104.6841563 109.903421 N O H N - -0 -0.3. 108.4 108.7 N -1.7859388761 106.6729323 108.4588712 H OH O9 '00 -11.55743971: 96.56812237' 108.1255621 WO 2011/094708 PCT/US2011/023220 HN-N HO OH -16.27483907 89.94614004 106.2209791 N OHN ~9.463295931' 115.1848233 105.72152741 7.035327937 98.55501099 105.5903389 N N NH, 0N2 N 10.7155014 114.7223418 104.0068404
N
0 SN 0 2.332623997 103.4341651 101.1015411 NH HN NH 14.04124001: 112.8657315 98,82449146 -...... .......-- --.----.................. ...... ... 0 CI N) H S NO" HO Ho -10.86859971| 87.36357022 98.23216992 96 WO 2011/094708 PCT/US2011/023220 CI 00 NH ...- N -14.50299142 83.61559031 98.11858173 C0 7 ,~ NNO N -10.5954323 87.16205145 97.75748375 1 H -9.610778443 87.82745228 97.43823072 OH HO 00 HH OH OH 3.955080904 101.0243434 97.0692625 0 0 N -18.5 78.1 96.:6 N HON OH OH2.606828112, 96.58770003 93.98087192 OH 10.32290702 104.1661092 93.84320213 97 WO 2011/094708 PCT/US2011/023220 F F N N o10 91 NN HiN- 0 o6.6 99.9 93.2 NN S4.8951710591 96.11650485 91.01479426 7.037265168 97.35012677 90.3128816 HO 0 0 00 H o OH OH 1.259544221t 90.578025721 89.31848151 0 14.82516366 103.9217319 89,09656823 HO / OH Ho qO OH OH 16.68871081: 105.3416001 88.65288929 ON 00 0 0 114.6! 101.31 86.7 98 WO 2011/094708 PCT/US2011/023220 O N N 0 0 oN -13.00667806 71.10363607 84.11031413 -N N 30.17353579 114.1379598 83.964424 N N NN 0 O NH 16.19966207 99.90532748 83.70566541 ~ - - NO HOO NO 0 H H 9.240186268 92.49338093 83.25319466 -N N 3.36867863 86.24446993 82.8757913 HN S NH 00 19.68883273~ 102.4094424 82.72080968 PON 20.72333282 103.4206261 82.69729329 99 WO 2011/094708 PCT/US2011/023220 0 6.516370589 89.09642401 82.58005342 0 0 0 N. N 0 N 0 -7.07177814 75,49565787 82.56743601 OH NON 0 H i 2 7 NO ON 15.93536133& 98.2573418 82.32198048 NN 00 'B7' 0N /0 N. 0l 22.9770388: 104.0060981 81.02905928 11492.21 80.8 100 WO 2011/094708 PCT/US2011/023220 CI OH '0 -3.913592369 75.92785571 79.84144808 N - O 0 0 F 21.93834459 101.5900478_ 79.65170319 N ,~ N 3i 33.27029276 112.3457833 79.07549058 N 0 NHO -2.04714193 75.96629122 78.01343315 N OH 30.19710502: 107.6879038 77.4907988 Ho Q A0 19.7020024 96.38730675 76.71710652 Br Q Q 0 O OH N 13.3744856: 90.06707122 76.69258563 s HO - ----- 0 26.07784431 102.7683663 76.69052194 101 WO 2011/094708 PCT/US2011/023220 HD 0 0 NZ0 O/ N/ 0 \ N 21.84 98.2 76.4 --- -- -- -- - - - - - - - . --- -- -- ------- --- - - - 0 ~0 O N N 19.48 95.8 76.41 0 NH ~N 0 00 19.52748 96.385598 7 6.7951709 0 1.90128: 97,1843532 75.37408823 F F 0 N 0 21 .58274889 96.347855981 74.79510709 102 WO 2011/094708 PCT/US2011/023220 0 N> NH 24.59486004! 99.32600497 74.73114493 N cll HO 15.04465661 89.36779259 74.32313598 0T NN NH 18.96382387 92.90700473 73.94318087 N 0N cl cl c1 N N 15.57226143 89.4401828 73.86792137 HHN s 30.229510381 13.1376448 7.16814 N N %000 N.* Na* 27.20036677' 100.4228001 73.22243335 00 37.92480367: 111.0248078 73,10000413 00 0HNQO0 0 NN / s8.332108744 81.171274331 72.839165591 103 WO 2011/094708 PCT/US2011/023220 OH 0 o 12.58907363 84.89878885 72.30971522 OH OH 35.01128141 106.8345939 71.8233125 F N OH HN N HO 42.48636709 113.7228826 71.23651547 OH -5.849688118 65.32554791 71.17523603 14.29140445 85.26500639 70.97360194 00 N 58.7 129.5 70.8 H F F 1 F 11.97648788 82.61082938 70.6343415 N NN HN N N0 14.3007360 84.68236855 1 70.381632481 104 WO 2011/094708 PCT/US2011/023220 -N N NH -WO NH 738.57217917 107.8998073 69.32762815 N NH 38.84682418 107.804978 69.20367362 o o NH N N a 0 18.37621111 107.85041923 69.29327162 0 01 21.28742515' 90.20742087 68.91999572 O 0 NNH NH 00 19.372211111 87.66541 8231 68.29320712 105 WO 2011/094708 PCT/US2011/023220 HO 0 NH 14.6 82.8 68.3 HO OH /OH HO/ O OH OH 34.13126397 102.36293311 68.23166909 --
--------.-
N O NH 0 11.72800505 79.87789988 68.14989482 N SH NH N 0 39.1 107.0 67.9 N NNNH N 25.28012412 92.88964225 67.60951814 0 HN 0 34.53258845: 102.0162884 67.48369999 0 S 0 H 0 IHN-~~ 23.0 89.9 66.9 106 WO 2011/094708 PCT/US2011/023220 HO 0 0 037.92480367: 104.5573433 66.6325396 l00 N NH 0 43.2 109.5 66.3 cl o00 N 30,47645315, 96.72727273 66.25081958 N HO I
NH
2 ;Ho S 34.54623163 100.760843 66.2146114 s ci 23.45468053 89.61072441 66.15604388 so 0 24.12504492 90.1231625 65.99811758 N 0 N 0 OH 27.16644285 93.0177803 65.85133746 107 WO 2011/094708 PCT/US2011/023220 N NNH HN N NH N N ;N\I a___ -6.097006083: 57.6845011 65.78150718 NN Ho A /N s 66.13604597 131.2029473 65.06690133 clT * 0 Ho 11.19902121 76.15107324 64.95205204 s N 0 4.577793748 69.52721494 64.94942119 NH S 18.95094399: 83.66485345 64.71390946 00N " 0 26.7 91.4 64.7 cl 34.3965106: 99.00834642 64.61183562 31.16639478 95.42026511 64.25369033 00 HO / OH 32.90443509 97.09434568 64.18991059 108 WO 2011/094708 PCT/US2011/023220 HN HO 0 36.11902501 100.2785294 64.15950436 N HN 0 N HN 35,72624681: 99.74101397 64.01476715 QN 21.78361457 85.37461774 63.59100317 N N N NH N\Q 39.7488359: 103.3154122 63.56657629 F F NH F N HN- 41.28528975 104.7348973 63.44960756 0 N "N 43.51306119 106.9095962 63.39653504 N--NH N\ 18.57176712 81.71632703 63.14455991 109 WO 2011/094708 PCT/US2011/023220 N\ NNH
HN
29.27084059 92.34063996 63.06979937 N OH 3135543 .441842001 63.02290508 NH 0 0 48.21516581 111.214653 62.99948715 OH o NH 27.71898883 90,70584478 62.9868559 N 0 C .~2.4549426 101.45158 62.976064224 0 0 -19.61126884: 43.27239348 62.88366232 0 N NH N N 6,012957705! 68.851 83202 62.83887431 0 N0 NH N O -H 9129.454926621; 92.215568861 62.76064224 110 WO 2011/094708 PCT/US2011/023220 [0 N 0 I N s 00 35.6 98.3 62.7 OHOH 43.7012494; 106.4084449 62.70719545 40.93873164: 103.0201067 62.08137505 0 --1-------- -. 93.01166131 61.79901285
N
OH 0 39.52157023 101.2560945 61.73452431 N NSQ 6 D OH 0 59.441744; 120.9256794 61.48393538 0O \\S 00 25.38058602 86.7447645 61.36417848 N 39.32183657 100,3628503 61.04101373 0 NH9 N18.435957011 79.39308398 60.95712697 111 WO 2011/094708 PCT/US2011/023220 HO -29.64270278 31.23996145 60.88266423 ,ON0 * 0 27.27621091 88.11755764 60.84134673 0 Q s O N o b>-s N 0 C a N- N C 37.6 98.3 60.7 N NQ 4.673280876i 65.02894576 60.35566489 * N N HN 0 41.8167411 102.1683264 60.35158527 0 N .0 * 39.931613771 99.39343581 59.46182205 Cl 0 OH HO Cl CI CIC 41.01271009 100.3606236 59.34791354 112 WO 2011/094708 PCT/US2011/023220 /0 P 47.18965126 106.53202641 59.34237511 0 HN 0 36.55154869 95.64034877 59.08880009 OH N 41.78912826 100.8274721 59.03834381 0 Nz NH 34.66750489 93.68924174 59.02173685 Br 18.74037573i 77.59057823 58.8502025 HN NH 22.81374655 81.47543659 58.66169004 113 WO 2011/094708 PCT/US2011/023220 F NH NH 0 N i-N ~ 39.52194519 98.09873249 58.5767873 -------- oH O\H 4 N os F 39.11594696 97.63720151 58.52125455 0 S s HO o 30.40891164 88.85677858 58.44786694 - N OH N 25.20612485, 83.4987795 58.29265464 0 ~0 NH S Ol 0 0 43.16379248 101.2275149 58.06372239 N 31.4290114 89.23693465 57,80792326 114 WO 2011/094708 PCT/US2011/023220 N 0 00 Br HN 0 38.17542436 95.91685226 57.74142791 F F !F HN N 27.92957859 85.64814815 57.71856956 48.94267421: 106.2615101 57.31883592 NN Cl N N 32.32116549 89.4407446 57.11957911 NO 38.73289121, 95.62561095 56.89271974 A 0 NH N 0 BI~ 45.19897498 102.0166733 56.81769831 0 35.395828491 92.03372469 56.6378962 115 WO 2011/094708 PCT/US2011/023220 N HO OH 34.63356974 90.94954311 56.31597337 N 44.3733406, 100.671 5454 56.29820482 N 0 I$ N 0 H 41.985733 98.20470972 56.21897672 F F F F N N F F F s 45.61615856 101.6646949 56.04853639 N C * 0 F 41.13775626 97.06777083 55.93001457 NHz 7.821811681 63.5443038 55.72249212 0 O N N 45.56074766 101.2544661 55.69371839 N 43.76933274 99.37348265 55.60414991 116 WO 2011/094708 PCT/US2011/023220 0 N H N F F F 43.36958596 98.96808255 55.5984966 35.11114267 90.69859962 55.58745694 HN ObO 29.48940031 85.03813193 55.54873162 NN 0 35.03258269 90.44736221 55.41477952 _ F NN Q 0, 55.47976701 110.818343 55.33857603 S NH 38,04746419 93.34466638 55.29720219 N s N N N 40.13238539 95.37388609 55.2415007 117 WO 2011/094708 PCT/US2011/023220 44.19099554 99.42563929 55.23464375 S33.24656324: 87.76949553 54.52293229
N
00 N 1 36.15465782; 91.34577213 55.1911431 HN' N N 1 27.2754491! 82.27419222 54.99874311 N OH N 36.59699818: 91.44689379 54.84989561 N H N 27.2785081, 72.289292 54.487421 0 36 2.59694074 7685712 54.5495 01 o NH 0 0 19.17808219! 73.82692962 54,64884742 04 0 21.54074074! 76.08572124 54.54498051 118 WO 2011/094708 PCT/US2011/023220 N F 45.20486556 99.55872914 54.35386358 32.60195759: 86.63771915 54.035761571 N F0 328.0615 82.6371915 .842 NOP oN 2H3081052 84.78772647 53.9714065 41.22497055~ 95.08543531 53.86046476 0 N NN 42.82815987 96.57675493 53.74859506 H N KN N 10 N 52.01193335 105.6743612 53.6624278 119 WO 2011/094708 PCT/US2011/023220 OH 10 43.85063378 97.46473998 53.61410621 S N -H 39.74584291 93.29913695 53.55329404 OH NO 41.15745598; 94.72268477 53.56522879 H OH OH 0 OH -19.812909 33.73781755 53.55076845 i0 FN o0 N NO O 40.42061339! 93.71157747 53.29096408 50.38587118 103.6178964 53.23202524 120 WO 2011/094708 PCT/US2011/023220 0 TO NQ 45.37762426: 98.52069172 53.14306746 OH NH QOH 36.25704957 89.38134811 53.12429854 S N o 1N '0 30.70619785 83.66680278 52.96060492 HoH N 55.56846133: 108.4623958 52.91393446 CH 0 N H 0 N 36.80576864i 89.70132202 52.89555338 N 38.8244915 91.9237753 52.77192788 HNS HN1 oH 5o.816419; 103.41218171 52.59549746 121 WO 2011/094708 PCT/US2011/023220 0 46.42363385 99.00409172 52.58045787 N 69.985743231 122.2854715 52.29972831 /N N S ON 0 25.26217665 77.54573418 52.28355753 0 HN 0 NH S0 39.96352925 92.21643287 52.25290362 * F F. NH 47.00574838 99.25113873 52.24539035 0 53.49055971 105.6295695 52.13900976 122 WO 2011/094708 PCT/US2011/023220 a C NH 0 N 00 N 49.44050318: 101.5763783 52.13587515 N s 39.83535868 91.73339804 51.89803936 SH 54.02808574: 105.7595451 51.73145935 NQ N 51.20524073 102.9357651 51.73052441 sN-NH NH 43.22472716 94.84355045 51.61882329 0FF F 42.5929832 94.16497422 51.57199103 Sr
H
2 N 32.55627595 83.96631306 51.41003711 123 WO 2011/094708 PCT/US2011/023220 QN N 0 0 N 47.31068916 98.28460368 50.97391452 46.55678968 97.50512926 50.94833958 0 N 00 34.10555385 85.00081606 50.89526221 HN N 0 HO OH F30.59011861 81.340230061 50.75011146 0 55.74433657, 106.4705403 50.72620373 N 44.76047904: 95.3640195 50.60354046 SN R 0 o -20.05671367 30.41972806 50.47644174 N 0 00 35.60617193 85.8825454 50.27637346 124 WO 2011/094708 PCT/US2011/023220 NF 57.07388105 107.3051263 50.2312452 rO a 48.7076967 98.89474361 50.1870469 NH NN HNQ 56.5514328 106.3303342 49.77890139 0 CH H 0% 56.60157162 106.2747212 49.67314961 0~ 0** HNN 0rHN 00 33.00999412i 82.65729799 49.64730387 125 WO 2011/094708 PCT/US2011/023220 - / 0 N o 0 N 29.3347706 78.76829966 49.43352911 HN cHNQo 33.27874504 82.61218664 49.33344159 N N N0 750.5499649 99.62531364 49.27534875 NN NN NN 30.48780488 79.68386424 49.196059361 O C5 / 0 Br NH 47.95352324 96.90361633 48.95009309 0 N N 35.81991695 84.74370394 48.92378699 SN -ko N 47.9673093 96.80006481 48.8327555 0 F F ON FQ 33.22160149 81.90084605 48.67924456 126 WO 2011/094708 PCT/US2011/023220 00 48.95344507 97.58836088 48.63491581 CH N 44.23800949; 92.39348471 48.15547522 Ho215.6015433 263.7374061 48,13586273 N 56.33127545: 104.43159921 48.10032378 127 WO 2011/094708 PCT/US2011/023220 O 55.14812663 103.2306124 48.08248577 0 NH to 64.63766028 112.7047864 48.0671261 44.405779566 92.470846711 48.06506715 S0 N ) N 00 51.18862475 99.22340759 48.03478284 N N ON 20.34336068: 68.23874445 47.8953837 44.3557943, 92.238369731 47.882575441 00 100 446.409546 92.7467 4.76509742 ICHN--NH2 cl 55.76098501 103.5302403 47.76925533 128 WO 2011/094708 PCT/US2011/023220 48.75160508 96.45841953 47.70681445 00 N 0.s 48.26958106 95.97238934 47.70280828 0O 0 69.86140798 117.5434343 47.68202636 CI N Q 48.52722404 96.19903793 47.67181389 40.64114251 88.27679138 47.63564887 S0 N N 43.06355747 90.61530929 47.54995182 HN HN F / N N 40.42192793! 87.79749734 47.37556941 N 62.7184466 110.0825659 47.36411929 129 WO 2011/094708 PCT/US2011/023220 0 s SNH2 00 s N 0 58.50862999 105.8574397 47.34880968 0 34.93352497 82,24076281 47.30723784 0 HN 53.71064468 101.0010865 47.29044177 FQ Ho OH 28.42089641 75.68202804 47.261131631 o HN 0 HS F 55.0937101 102.2099448 47.11623465 N 30.48240503 77.54573418 47.06332914 00 N N N51.13822161 98.19719754 47.05897593 sF 00 65.41604755 112.4344762 47.01842869 130 WO 2011/094708 PCT/US2011/023220 HO 0 Ho HO NH 00 N 48.322054 95.33022533 47.00817133 N 35.82692457 82.4672171 46.64029252 so 45.64428312 92.1013059 46.45702277 S N NH 0 49.68408533 96.06979643 46.38571109 H N HS 48.65415987 95.02703588 46.37287601 \s OH 58.11789038 104.3981674 46.28027705 SS ss N 0 40.50995892 86.74650699 46.23654806 OH 0 -H 44.357572821 90.48873778 46.13116496 x ~-N N 47.01730419i 93.0593376 46.042033411 131 WO 2011/094708 PCT/US2011/023220 OH N 63.36025402 109.3342199 45.97396591 F F F~co N 1 40.75591985 86.72661643 45.97069657 NH o 66.09053804 111.9999168 45.90937874 0
N-
N 69.53461354 115.1985743 45.66396079 56.10428305 101.763264 45.65898096 0 NQ 42.83942002 88.37759P42 45.5381704 0 H 50.06136852! 95.57695446 45.51558595 132 WO 2011/094708 PCT/US2011/023220 N N N N 52.76268116 98.25183684 45.48915568 -N N N 53.00666405 98.46315619 45.45649214 HO N oH 1 47,98902391: 93.41583758 45,42681367 oH HN N 58.33277892 103.7511722 45.41839332 N N 55.45434348 100.8550361 45.4006926 00 N0 0__ 10 68.79611916 114.1804937 45.38437457 S H 47.68581216 92.92784163 45.24202948 133 WO 2011/094708 PCT/US2011/023220 NH N 0 0 N / 37.60579356 82.80346821 45.19767465 N 49.80397458 94.9926722 45.18869762 N, N N \N 52.42631325 97.498129831 45.07181658 134 WO 2011/094708 PCT/US2011/023220 TABLE 1- 0 Structure Structure 0 0 <I N H S N ~NH HN S N 0 0N HN O 0 H Clc HO OH 135 WO 2011/094708 PCT/US2011/023220 TABLE 1- P HOH OH HO Myricetin H OH OH34.43163 100.6083 6.216114 H0 0/ OH HO O OH OH Quercetin 16.68871081 105.3416001 88.65288929 N HH HO NH Tyrphostin 47 34.54623163 100.760843 66.2146114 00 O Manoalide OH 35.01128141 106.8345939 71.8233125 U73122 56.60157162 106.2747212 49.67314961 OOH O 0 0 0 OH Balcailen 0H10.32290702 104.1661092 93.84320213 O HO O 000 % OH Dyclonine OH 1.259544221 90.57802572 89.3184815 136 WO 2011/094708 PCT/US2011/023220 Cl Cl C, C, CIOs Bithionol Na N. 27.20036677 100.4228001 73.22243335 Oo 0 Gossypol 3.955080904 101.0243434 97.0692625 OH HO ICI Hexachlorophene 41 .01271 009 100.3606236 59.34791 354 00 HO Celastrol */32.90443509 97.09434568 64.18991059 HO OH HOq HO H OH H O O 0 H OH Tannic Acid ~~~HO H 1595313 982748 823184 130 HO OH0 OO 0 O O HO Tannic Acid HO OH 1 15.935361331 98.25734181 82.32198048 137 WO 2011/094708 PCT/US2011/023220 REFERENCE$ 1. 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Claims (17)
1. A method of selectively modulating MCL- 1 in cells, comprising contacting said cells with one or more compounds of formula: 5 A) R1 N (Z')q R 2 x or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein: X is =O or -O-R 10 R 1 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, -S-R 2a, -S0
2 -R2a R2 is hydrogen, halogen, -O-R 2a, -NH-R 2a, -S-CN, -S-R 2a, -S-CH 2 -R2a or S0 2 -R2a 15 R2a is C1-C 8 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; R3 is hydrogen, C 1 -C 8 alkyl substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or 20 unsubstituted heterocycloalkyl; each occurrence of n is independently an integer from 0-4; each occurrence of q is independently an integer from 0-1; and each occurrence of Z and Z' is independently halogen, hydroxyl, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, or C 1 -C 6 alkoxy, substituted or unsubstituted aryl, 141 substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; thereby regulating MCL- 1 in said cell. 5 2. The method of claim 1, wherein said modulating MCL-1 comprises modulating apoptotic cell death, thereby regulating apoptotic cell death in said cells.
3. The method of claim 1, wherein said modulating MCL-1 comprises modulating autophagy, thereby regulating autophagy in said cells. 10
4. The method of claim 1, wherein said modulating MCL-1 comprises modulating necrotic cell death.
5. The method of claim 1, wherein said modulating MCL-1 comprises 15 modulating metabolism in a cell, regulating energy production and consumption to effect cell viability in said cell.
6. The method of claim 1, wherein said modulating MCL-1 comprises modulating cell division in a cell, thereby regulating proliferation in said cell. 20
7. The method of claim 1, wherein said modulating MCL-1 comprises modulating transcription in a cell, thereby regulating transcription in said cell.
8. The method of claim 1, wherein said modulating MCL-1 comprises 25 modulating RNA processing in a cell, thereby regulating RNA processing in said cell.
9. The method of claim 1, wherein said modulating MCL-1 comprises modulating differentiation in a stem or progenitor cell, thereby regulating the lineage and phenotype in cell. 30
10. The method of claim 1, wherein said modulating MCL-1 comprises modulating multimerization of MCL- 1 in a cell, thereby regulating multimerization of MCL-1 in said cell. 142
11. A method of treating a disease or disorder associated with MCL- 1, wherein said treating comprises modulating MCL- 1 and said disease or disorder is selected from the group consisting of a hyperproliferative disorder, angiogenesis disorder, inflammatory disease or disorder, infectious disease or disorder, cell cycle regulation 5 disease or disorder, autophagy regulation or disorder, and an autoimmune disease or disorder; comprising administering to a mammal in need thereof, a therapeutically effective amount of one or more compounds of formula A: R1 N (Z')q R 2 (Z) x 10 or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein: X is =O or -O-R R 1 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, 15 -S-R 2a, -S0 2 -R2a R2 is hydrogen, halogen, -O-R 2a, -NH-R 2a, -S-CN, -S-R 2a, -S-CH 2 -R2a or S0 2 -R2a R2a is C1-C 8 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or 20 unsubstituted heterocycloalkyl; R3 is hydrogen, C 1 -C 8 alkyl substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; each occurrence of n is independently an integer from 0-4; 25 each occurrence of q is independently an integer from 0-1; and 143 each occurrence of Z and Z' is independently halogen, hydroxyl, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, or C1-C 6 alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl. 5
12. The method of claim 11 wherein the hyperproliferative disorder is cancer.
13. The method of claim 11 wherein the hyperproliferative disorder is refractory cancer. 10
14. The method of claim 12 wherein the cancer is a cancer of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid or a distant metastasis of a solid tumor.
15 15. The method of claim 12 wherein the cancer is a lymphoma, sarcoma, or leukemia.
16. A method of sensitizing a cell to treatment by a secondary active ingredient comprising administering to a cell a sensitizing amount of one or more compounds of 20 formula A R1 N (Z')q R 2 x or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein: X is =O or -O-R 144 R 1 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, -S-R 2a, -S0 2 -R2a R2 is hydrogen, halogen, -O-R 2a, -NH-R 2a, -S-CN, -S-R 2a, -S-CH 2 -R2a or 5 SO 2 -R2a R2a is C1-C 8 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; R3 is hydrogen, C 1 -C 8 alkyl substituted or unsubstituted aryl, substituted or 10 unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; each occurrence of n is independently an integer from 0-4; each occurrence of q is independently an integer from 0-1; and each occurrence of Z and Z' is independently halogen, hydroxyl, C 1 -C 8 alkyl, C 2 -C 8 15 alkenyl, C 2 -C 8 alkynyl, or C1-C 6 alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl.
17. The method of claim 16, wherein the secondary active ingredient is a death 20 receptor stimulant, an antacid, an antibiotic, an antiemetic agent, an antidepressant, an antifungal agent, an anti-inflammatory agent, an antiviral agent, an anticancer agent, an immunomodulatory agent, a beta-interferon, a hormone or a cytokine. 25 145
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JP2013518816A (en) | 2013-05-23 |
EP2528893B1 (en) | 2018-10-10 |
US10000511B2 (en) | 2018-06-19 |
EP2528893A2 (en) | 2012-12-05 |
JP5937968B2 (en) | 2016-06-22 |
WO2011094708A3 (en) | 2012-01-12 |
JP2016183175A (en) | 2016-10-20 |
US20150315211A1 (en) | 2015-11-05 |
CA2787784A1 (en) | 2011-08-04 |
EP3138838A1 (en) | 2017-03-08 |
EP2528893A4 (en) | 2013-07-24 |
US20130035304A1 (en) | 2013-02-07 |
JP6227707B2 (en) | 2017-11-08 |
WO2011094708A2 (en) | 2011-08-04 |
AU2011210567A1 (en) | 2012-08-09 |
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